Heterocyclic 15-substituted-ω-pentanorprostoglandins

ABSTRACT

The 15-substituted- omega -pentanorprostaglandins and various intermediates employed in their preparation. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins, but exhibit a greater tissue specificity of action.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of our U.S. patentapplications Ser. No. 271,220 filed July 13, 1972 and now abandoned andSer. No. 425,517 filed Dec. 17, 1973, and now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to certain novel analogs of the naturallyoccurring prostaglandins. In particular, it relates to novel15-substituted-ω-pentanorprostaglandins and various novel intermediatesuseful in their preparation.

The prostaglandins are C-20 unsaturated fatty acids which exhibitdiverse physiological effects. For instance, the prostaglandins of the Eand A series are potent vasodilators (Bergstrom, et al., Acta Physiol.Scand. 64:332-33 1965 and Bergstrom, et al., Life Sci. 6:449-455, 1967)and lower systemic arterial blood pressure (vasodepression) onintravenous administration (Weeks and King, Federation Proc. 23:327,1964; Bergstrom, et al., 1965, op. cit.; Carlson, et al., Acta Med.Scand. 183:423-430, 1968; and Carlson, et al., Acta Physiol. Scand.75:161-169, 1969). Another well known physiological action for PGE₁ andPGE₂ is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).

Still another important physiological role for the naturalprostaglandins is in connection with the reproductive cycle. PGE₂ isknown to possess the ability to induce labor (Karim, et al., J. Obstet.Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion(Bygdeman, et al., Contraception, 4, 293 (1971) and to be useful forcontrol of fertility (Karim, Contraception, 3, 173 (1971)). Patents havebeen obtained for several prostaglandins of the E and F series asinducers of labor in mammals (Belgian Pat. No. 754,158 and West GermanPat. No. 2,034,641), and on PGF₁, F₂, and F₃ for control of thereproductive cycle (South African Pat. No. 69/6089). It has been shownthat luteolysis can take place as a result of administration ofPGF₂.sub.α [Labhsetar, Nature 230 528 (1971)] and hence prostaglandinshave utility for fertility control by a process in which smooth musclestimulation is not necessary.

Still other known physiological activities for PGE₁ are in theinhibition of gastric acid secretion (Shaw and Ramwell, In: WorcesterSymp. on Prostaglandins, New York, Wiley, 1968, p. 55-64) and also ofplatelet aggregation (Emmons, et al., Brit. Med. J. 2:468-472, 1967).

It is now known that such physiological effects will be produced in vivofor only a short period, following the administration of aprostaglandin. A substantial body of evidence indicates that the reasonfor this rapid cessation of activity is that the natural prostaglandinsare quickly and efficiently metabolically deactivated by β-oxidation ofthe carboxylic acid side-chain and by oxidation of the 15α-hydroxylgroup (Anggard, et al., Acta. Physiol. Scand., 81, 396 (1971) andreferences cited therein). It has been shown that placing a 15-alkylgroup in the prostaglandins has the effect of increasing the duration ofaction possibly by preventing the oxidation of the C15-hydroxyl [Yankeeand Bundy, JACS 94, 3651 (1972)], Kirton and Forbes, Prostaglandins, 1,319 (1972).

It was, of course, considered desirable to create analogs of theprostaglandins which would have physiological activities equivalent tothe natural compounds, but in which the selectivity of action and theduration of the activity would be increased. Increased selectivity ofaction would be expected to alleviate the severe side effects,particularly gastrointestinal side effects, frequently observedfollowing systemic administration of the natural prostaglandins (Lancet,536, 1971).

SUMMARY OF THE INVENTION

These needs are met by the novel compounds of this invention, the15-substituted-ω-pentanorprostaglandins in which the substituent inquestion is of the structure:

    Ar--(CH.sub.2).sub.n --

wherein Ar is α- or β-furyl; α- or β-thienyl; and n is an integer from 0to 5, with the proviso that when n = 0 said prostaglandin is a 13,14dihydro prostaglandin, and in which the remaining 15-hydrogen may bereplaced by a 15-lower alkyl group if desired.

In addition to the 15-substituted-ω-pentanorprostaglandins wherein theprostaglandin is PGF₁.sub.α, PGF₁.sub.β, PGE₁, PGA₁ : 13, 14-dihydroPGF₁.sub.α, PGF₁.sub.β, PGE₁, and PGA₁ ; PGF₂.sub.α, PGF₂.sub.β, PGE₂,PGA₂ ; 13,14-dihydro PGF₂.sub.α, PGF₂.sub.β, PGE₂, and PGA₂ ; 15-loweralkyl derivatives of the above compounds, this invention furthercomprises a compound of the structure: ##EQU1## wherein Ar is α- orβ-furyl; α- or β-thienyl; and n is an integer from 0 to 5, a usefulreagent for preparation of the novel prostaglandins; and usefulintermediates for these prostaglandins as follows:

a compound of the structure: ##SPC1##

a compound of the structure: ##SPC2##

wherein R is hydrogen or lower alkyl; and Q is hydrogen orparabiphenylcarbonyl;

a compound of the structure: ##SPC3##

wherein THP is tetrahydropyranyl, n is an integer from 0 to 5; Z is asingle bond or a trans double bond with the proviso that when n is O,Zis a single bond, and X is =O ##EQU2##

a compound of the structure: ##SPC4##

wherein w is a single bond or a cis double bond and Z, THP, R, Ar and nare as previously defined;

a compound of the structure: ##SPC5##

wherein W, Z, THP, R, Ar and n are as previously defined,

and especially 16-α-thienyl-ω-tetranor PGE₂ ; 16-α-thienyl-ω-tetranorPGE₁ ; 16-β-thienyl-ω-tetranor PGE₂ ; 17-α-thienyl-ω-trisnor PGE₂ ;17-α-furyl-ω-trisnor PGE₂ ; 17-α-furyl-ω-trisnor PGF₂.sub.α and17-α-thienyl-ω-trisnor PGE₂.sub.α 17-β-furyl-ω-trisnor PGE₂ ;17-β-furyl-ω-trisnor PGF₂.sub.α ; 17-β-thienyl-ω-trisnor PGF₂.sub.α ;17-β-thienyl-ω-trisnor PGE₂ and the C₁₅ epimers of these compounds.

It will be understood by those skilled in the art that in structuresdepicting hemiacetals, no sterochemistry is implied at the lactolcarbon.

It will be further understood that as herein used the expression"prostaglandin of the `zero` series, " for example PGE₀, refers toprostaglandin in which the 5-6 and 13-14 double bonds have beensaturated; i.e.: PGE₀ is 5-6, 13-14, tetrahydro PGE₂. In addition, thephrases "zero series", "one series " or "two series" as herein employedrefer to the degree of unsaturation in the side chains, e.g. PGE₂, PGA₂,PGF₂.sub.α, and PGF₂.sub.β are prostaglandins of the "two series"whereas PGE₁, PGF₁.sub.α, PGF₁.sub.β and PGA₁ are prostaglandins of the"one series". Furthermore, as herein employed the phrase lower "alkylgroup" refers to alkyl groups containing from 1 to 4 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

As shown in Scheme A, the first step (1→ 2) is the condensation of theappropriate ester with a dialkyl methylphosphonate to produceketophosphonate 2. Typically, the desired methyl ester is condensed withdimethyl methyl phosphonate.

In 2 → 3 the ketophosphonate 2 is caused to react with the known [Coreyet al., J. Org. Chem. 37, 3043 (1972)] aldehyde H to produce, afterchromatography or crystallization, the enone 3.

The enone 3 can be converted to a mixture of tertiary alcohols 13 and 14by reaction with the appropriate lithium alkyl or grignard reagent andthe isomeric 13 and 14 can be separated by column or high pressureliquid chromatography. The enone 3 can be reduced with zinc borohydrideto a mixture of alcohols, 4 and 5 which can be separated as above.Lithium triethyl borohydride is especially preferred when 1-2 reductionis desired. In this reaction ethers such as tetrahydrofuran or 1,2dimethoxy ethane are usually employed as solvents. Furthertransformations of 4 are shown on Scheme B.: ##SPC6##

4→6 is a base catalyzed transesterification in which thep-biphenyl-carbonyl protecting group is removed. This is mostconveniently conducted with potassium carbonate in methanol ormethanol-tetrahydrofuran solvent. 6→ 7 involves the protection of thetwo free hydroxyl groups with an acid-labile protecting group. Anysufficiently acid labile group is satisfactory; however, the most usualone is tetrahydropyranyl, which can be incorporated in the molecule bytreatment with dihydropyran and an acid catalyst in an anhydrous medium.The catalyst is usually p-toluenesulfonic acid. ##SPC7##

7 → 8 is a reduction of the lactone 7 to the hemiacetal 8 usingdiisobutyl aluminum hydride in an inert solvent. Low reactiontemperatures are preferred and -60° to -70°C are usual. However, highertemperature may be employed if over-reduction does not occur. 8 ispurified, if desired, by column chromatography.

8 → 9 is a Wittig condensation in which hemiacetal 8 is reacted with(4-carbohydroxy-n-butyl)triphenylphosphonium bromide in dimethylsulfoxide, in the presence of sodium methylsulfinyl methide. 9 ispurified as above.

The conversion 9 → 12 is an acidic hydrolysis of the tetrahydropyranylgroups. Any acid may be used which does not cause destruction of themolecule in the course of the removal of the protecting group; however,this is accomplished most often by use of 65% aqueous acetic acid. Theproduct is purified as above.

9 → 10 is an oxidation of the secondary alcohol 9 to the ketone 10. Thismay be accomplished using any oxidizing agent which does not attackdouble bonds; however, the Jones reagent is usually preferred. Theproduct is purified as above.

10 → 11 is carried out in the same manner as 9 → 12. The product ispurified as above.

11 → 15 is an acid-catalyzed dehydration. Any acid may be used for theprocess which does not cause extensive decomposition of the product, butthe most usual procedure consists of dissolving 11 in an excess of 97%formic acid followed by dilution with ice water and extraction of theproduct after the starting material has been consumed. The product ispurified as above. ##SPC8##

As is illustrated in scheme C, 5, 13 and 14 may be substituted for 4 inscheme B to provide prostaglandin derivatives 12'-18'.

Scheme D illustrates the synthesis of precursors to the13,14-dihydro-15-substituted-ω-pentanorprostaglandins.

In 3 → 19 + 19' the enone 3 is reduced to the tetrahydro compoundthrough the use of any of the complex metal hydride reducing agents,LiAlH₄, NaBH₄, KBH₄, LiBH₄ and Zn(BH₄)₂. Especially preferred is NaBH₄.The products, 19 and 19', are separated from each other by column orhigh pressure liquid chromatography.

Furthermore, the compounds 4 and 5 of Scheme A can be reducedcatalytically with hydrogen to 19 and 19' respectively. The stage atwhich the double bond is reduced is not critical, and hydrogenation of 6or 7 of scheme B will also afford useful intermediates for the 13,14dihydro prostaglandin analogs of the present invention. This reductionmay be achieved with either a homogenous catalyst such astristriphenylphosphinerhodiumchloride, or with a heterogeneous catalystsuch as platinum, palladium or rhodium. In a similar way the precursorsto the 15-lower alkyl-15-substituted-ω-pentanorprostaglandins aresynthesized by substituting compounds 13 and 14 for 4 and 5respectively, in the synthesis just described. The conversion of 19,19', 20' and 20 to their respective prostaglandins follows the routeshown in scheme B when 4 is replaced by 19, 19', 20' and 20 to yield the13,14dihydro PGE₂, PGA₂ and PGF₂ series of prostaglandin derivativescontaining hydrogen or lower alkyl group at carbon 15. ##SPC9##

Scheme E illustrates the preparation of the various reduced15-substituted-ω-pentanorprostaglandin precursors:

19 → 22 is carried out as illustrated on Scheme B for 4 → 9. 22 can beused as both a precursor to a 13,14-dihydro15-substituted-ω-pentanorprostaglandin of the "2-series" or as anintermediate to 23, a precursor to a13,14-dihydro-15-substituted-ω-pentanorprostaglandin of the "1-series".22 → 23 is carried out by catalytic hydrogenation using the catalystdescribed for the reduction of 4 → 19 of Scheme D. Intermediates of thetype 21 are prepared by selective reduction of the 5-6 cis double bondat low temperature using catalysts such as those described for 4 → 19and 17 → 23. Especially preferred for this reduction is the use ofpalladium on carbon as a catalyst and a reaction temperature of -20°.Intermediates of the type 21 are not only precursors to15-substituted-ω-pentanorprostaglandins of the "1-series" through theroute 9 → 15 of scheme B, but also as a precursor to compounds of thetype 23 through the route already discussed for 22 → 23. Furthermore,the 15-substituted-ω-pentanorprostaglandins of the E₁ and F₁.sub.αseries may be obtained directly from the corresponding prostaglandinanalog of the "2-series" by first protecting the hydroxyl by introducingdimethyl isopropyl silyl groups, reducing selectively the cis doublebond, and removing the protecting group. ##SPC10##

The introduction of the protecting group is usually accomplished bytreatment of the prostaglandin analog with dimethyl isopropylchlorosilane and 1,1,3,3-tetramethyl-1,3-diisopropyl disilazane, thereduction is accomplished as discussed above for 9 → 21 and removal ofthe protecting group is accomplished by contacting the reduced protectedcompound with 3:1 acetic acid:water for 10 minutes or until reaction issubstantially complete.

The C₁₅ epimers of 21, 22 and 23 can be used as precursors to the 15-episeries of prostaglandin derivatives described above, and15-lower-alkyl-15-substituted-ω-pentanorprostaglandins reduced at the5,6 and/or the 13,14 position and their C₁₅ epimers can be prepared fromthe appropriately substituted analogs of 9 and 19 whose syntheses followthose of Scheme A and B.

13,14-dihydro-15-lower alkyl-15-substituted-ω-pentanorprostaglandins areavailable from the appropriately substituted precursors via Scheme E.

In the foregoing procedures, where purification by chromatography isdesined, appropriate chromatographic supports include neutral aluminaand silica gel and 60-200 mesh silica gel is generally preferred. Thechromatography is suitably conducted in reaction-inert solvents such asether, ethyl acetate, benzene, chloroform, methylene chloride,cyclohexane and n-hexane, as further illustrated in the appendedexamples.

In numerous in vivo and in vitro tests we have demonstrated that the newprostaglandin analogs possess physiological activities comparable tothose exhibited by the natural prostaglandins (see above). These testsinclude, among others, a test for effect on isolated smooth muscle fromguinea pig uterus, ginea pig ileum and rat uterus, inhibition ofnorepinephrine-induced lipolysis in isolated rat fat cells, inhibitionof histamine-induced bronchospasm in the guinea pig effect, on dog bloodpressure, inhibition of stress-induced ulceration in the rat, inhibitionof pentagastrine-induced hydrochloric acid reaction in rat and dog,inhibition of ADP- or collagen-induced aggreation of blood platelets,and on diarrhea in mice.

The physiological responses observed in these tests are useful indetermining the utility of the test substance for the treatment ofvarious natural and pathological conditions. Such determined utilitiesinclude: antihypertensive activity, bronchodilator activity, vasodilatoractivity, antithrombogenic activity, antiarrhythmic activity, cardiacstimulant activity, antiulcer activity, smooth muscle activity [usefulas an anti-fertility agent, for the induction of labor, and as anabortifacient], and anti-fertility activity through a mechanism notaffecting smooth muscle for example, luteolytic mechanisms.

The novel compounds of this invention possess highly selective activityprofiles compared with the corresponding naturally occurringprostaglandins and, in many case, exhibit a longer duration of action. Aprime example of the therapeutic importance of these prostaglandinanalogs is the efficacy of 16-α-thienyl-ω-tetranorprostaglandin E₂ whichexhibits hypotensive activity of enhanced potency and duration of actionas compared with PGE₂ itself. At the same time, the smooth musclestimulating activity is markedly depressed in comparison with PGE₃.

In a similar manner, the other 16-Ar-substituted PGE₂, PGE₁, PGE₀(tetrahydro PGE₂) and 13,14 dihydro PGE₂ analogs, as well as the novel15-substituted-ω -pentanorprostaglandins of the A series of the presentinvention exhibit desirable hypotensive activity. In addition, the16-Ar-substituted prostaglandins of the E and A series are potentinhibitors of gastric acid secretion, useful for the treatment of pepticulcers or gastric hyperacidity.

It should be noted that the 15-substituted13,14-dihydro-ω-pentanorprostaglandins of this invention are especiallyuseful owing to their increased selectivity. For example, the16-Ar-substituted-ω-tetranor-13,14-dihydro PGE₂, have highly selectivehypotensive activity whereas the 17-A-substituted-ω-trisnor 13,14dihydro have highly selective smooth muscle activity. Furthermore, the15-Ar-substituted-ω-pentanor 13,14-dihydro E₂ prostaglandins of thepresent invention are highly selective bronchodilator agents having nosignificant hypotensive activity. 17-α-furyl-ω-trisnorprostaglandinF₂.sub.α and E₂ exhibits outstanding smooth muscle stimulating activityuseful for fertility control, abortion and induction of labor, while atthe same time having reduced blood pressure effects. Furthermore, theother novel 17-substituted-ω-trisnorprostaglandins of the E and Fseries, of this invention, i.e. the 17,18,19 and 20-Ar-substitutedprostaglandins of the E and F series of this invention, exhibitdesirable smooth muscle stimulating activity. The16-Ar-substituted-ω-tetranorprostaglandins of the F series are usefulfor fertility control via mechanisms not affecting smooth muscle.

Furthermore, 16-β-thienyl-ω-tetranorprostaglandin E₂ exhibits highbronchodilator activity with reduced non-vascular smooth muscleactivity. In a similar fashion, the other16-Ar-substituted-ω-tetranorprostaglandin E₁ and E₂ analogs, forexample, the 16-α-thienyl-ω-tetranorprostaglandin E₁ of the presentinvention also display desirable bronchodilator activity.

The novel 15 lower alkyl compounds of this invention have the sameprofile of activity as the prostaglandin analogs of this invention,where R is hydrogen, from which they are derived. Their special utilityis concerned with the fact that their duration of action is muchincreased over the above said compounds, where R is hydrogen, and insuch cases where this is essential the 15 lower alkyl compounds areusually preferred.

Especially useful by virtue of their selective action are the13,14-dihydro 15-substituted-ω-pentanorprostaglandins. For example, the15-Ar-substituted 13,14-dihydro prostaglandins of the E series arehighly selective bronchodilators having no significant hypotensiveactivity. 16-Ar-substituted 13,14-dihydro tetranorprostaglandins of theE series are highly selective hypotensive agents with no significantbronchodilator activity. The 17-substituted 13,14-dihydro prostaglandinof this invention have selective smooth muscle stimulating activity.

All of the prostaglandins of this invention are also useful in the formsof their salts with pharmaceutically acceptable cations. Furthermore,esters at C₉, C₁₁ and C₁₅ in which the acyl group is lower alkanoyl,formyl, or benzoyl likewise share the utilities of the prostaglandinfrom which they are derived. In some cases a lower incidence ofundesirable side effects accompanies the use of these esters as comparedwith the corresponding unesterified prostaglandins. It is obvious to oneskilled in the art that these compounds include mono esters in the caseof a prostaglandin of the A series, diesters in the case ofprostaglandins of the E series and triesters in the case of the Fseries. Such esters are readily prepared by standard methods well knownin the art. The prostaglandin analogs which have a beta hydroxyl at C15and possess a C15 lower alkyl group have action which is similar totheir epimers. In some cases, however, the selectivity that thesecompounds display exceeds that of the epimeric compounds.

The new compounds of this invention can be used in a variety ofpharmaceutical preparations which contain the compound or apharmaceutically acceptable salt thereof, and they may be administeredin the same manner as natural prostaglandins by a variety of routes,such as intravenous, extra- and intra-amniotic, oral and topical,including aerosol, intravaginal, and intranasal, among others.

For induction of abortion an aqueous suspension of a17-substituted-ω-trisnorprostaglandin of the E or F series or tabletswould appropriately be administered at oral doses of about 1-20 mg.,with 1-7 doses per day being employed. For intravaginal administration asuitable formulation would be lactose tablets or an impreganted tamponof the same agent. For such treatments suitable doses would be fromabout 1-20 mg./dose for the 17-α -furyl PGE₂ derivative or from about10-200 mg/dose for the 17α-furyl PGF₂.sub.α derivative, with 1 to 7doses being employed.

Alternatively, for abortion, the 17-substituted-ω-trisnorprostaglandinscan be administered intra-amniotically at doses of 5-40 mg., 1- 5 timesper day, or infused intravenously at doses of 5-500 μg/minute for aperiod of from about 1-24 hours. Alternatively, for abortion, the17-substituted-ω-trisnorprostaglandins can be administered byextra-amniotic infusion at doses of 0.5-50 μg/min. for a period of from1- 24 hours.

Another suitable use for the 17,18,19 and 20-Ar-substitutedprostaglandin analogs of this invention is an inducers of labor. Forthis purpose an ethanol-saline solution of a 17-substituted-ω-trisnorPGF₂.sub.α or PGE₂ derivative can be employed as an intravenous infusionin the amount of from about 0.05-50 μg/minute for from about 1-10 hoursor orally in the form of capsules, tablets, solutions or suspensions atdoses of 0.005-5 mg. with 1-7 doses being employed.

To produce bronchodilation, an appropriate dosage form would be anaqueous ethanolic solution of a 13,14-dihydro15-Ar-substituted-ω-pentanorprostaglandin or 16-Ar-substituted-tetranorPGE₁ or PGE₂ employed as an aerosol using fluorinated hydrocarbons aspropellant in the amount of from about 3- 500 μg/dose with up to 16doses per day. To increase nasal potency, an appropriate dosage formwould be an aqueous solution of 16-Ar-substituted-tetranor PGE₁ or PGE₂,employed in the form of nose drops in the amount of 1-100 μg/dose asneeded.

The 16-Ar-substituted-ω-tetranorprostaglandins of the E,A, and13,14-dihydro E and A series are useful antiulcer agents. For thetreatment of peptic ulcers, these drugs are appropriately administeredorally in the form of aqueous suspensions, ethanolic solutions orpreferably in the form of capsules or tablets at doses of 0.001 to 0.10mg/kg per dose with up to 12 doses per day.

The 16-Ar-substituted-ω-tetranorprostaglandins of the E₁, E₂, E₀ and13,14-dihydro E and A series, are useful hypotensive agents. Fortreatment of hypertension these drugs could appropriately beadministered as an intravenous injection at doses of about 0.5-10 μg/kgor preferably in the form of the capsules or tablets at doses of 0.005to 0.5 mg/kg/day.

The above named 15-substituted ω-pentanorprostaglandin of the "one"series with the proviso that n = 1 to 5 may be prepared by the syntheticroute outlined in Scheme F. In the first step the hemiacetal U is causedto react with the 4 -carbohydroxy-n-butyl triphenylphosphonium bromideto produce intermediate W.

W→X involves treatment with diazomethane; followed by acetic anhydrideand pyridine; followed by reduction with palladium in carbon inethanol:acetic acid; followed by oxidation with dimethyl sulfoxide,dicyclohexylcarbodiimide, and pyridinium trifluoroacetate.

X→Y involves treatment with the sodium or lithium salt of theappropriate phosphonate (2) and purification by column chromatography.

X→X involves reduction with zinc borohydride or lithiumtriethylborohydride, hydrolysis, and separation of the C15 epimers bycolumn chromatography.

Z→Z1 involves treatment with dihydropyran with an acid catalyst followedby mild aqueous base hydrolysis.

Z1 PGF₁.sub.α, PGE₁, and PGA₁ 15-substituted-ω-pentanorprostaglandinsfollows exactly the same method as outlined for the PGF₂.sub.α, PGE₂,PGA₂ series above. ##SPC11##

Each of the novel compounds of the present invention are also useful inthe form of their C₁ esters. Examples of preferred esters are thosewherein the esterifying group is alkyl of from one to twelve carbonatoms; cycloalkyl of from three to eight carbon atoms; aralkyl of fromseven to nine carbon atoms; phenyl or β-naphthyl or mono substitutedphenyl or β-naphthyl wherein said substituent is:

halo, lower alkyl, lower alkoxyl or phenyl. Especially preferred are thep-biphenyl esters. These specific esters are valuable because they arevery easily crystallized, thereby affording the opportunity to recoverthem in highly pure form and outstanding yield whereas prostaglandins ingeneral ordinarily present severe crystallization problems. Thenewpara-biphenyl esters exhibit the activities of the correspondingparent novel compounds and in addition possess the advantage of aflattened activity versus time curve which is often advantageous. Theyfurthermore have reduced effects on gastrointestinal smooth muscle asevidenced by the reduction of side effects such as diarrhea. The newcompounds in the form of the para-phenylphenol esters are prepared byprocedures already described with appropriate substitution ofcorresponding intermediates in para-phenylphenol ester from for theintermediates employed in the foregoing reaction schemes. Thus, forexample, compounds 9 and 10 may be esterified with para-phenylphenol inthe presence of dicyclohexylcarbodiimide to provide para-phenylphenolesters of precursors to 15-substituted-ω-pentanorprostaglandinpara-phenylphenol esters. These can, through steps 9-12, 10-11 and11-12, be converted to the novel para-phenylphenol esters mentionedabove. Further, compounds 11, 12 and 15 can likewise be esterified withpara-phenylphenol and dicyclohexylcarbodiimide to provide the desiredesters. In addition, the para-biphenyl ester moiety can be introduced atan earlier stage by using in step 8-9 a tri-para-phenylphenol orthoester phosphonium bromide of the structure [(C₆ H₅)₃ P^(+CH) ₂ CH₂ CH₂CH₂ C(OR)₃ ]Br⁻ , wherein R equals para-phenylphenyl to provide thecorresponding ortho ester of 9 which can be carried though steps 9-15 toyield the desired para-phenylphenol esters.

To prepare any of the above dosage forms or any of the numerous otherforms possible, various reaction-inert diluents, excipients or carriersmay be employed. Such substances include, for example, water, ethanol,gelatins, lactose, starches, magnesium stearate, talc, vegetable oils,benzyl alcohols, gums, polyalkylene glycols, petroleum jelly,cholesterol, and other known carriers for medicaments. If desired, thesepharmaceutical compositions may contain auxiliary substances such aspreserving agents, wetting agents, stabilizing agents, or othertherapeutic agents such as antibiotics.

The following examples are merely illustrative, and in no way limit thescope of the appended claims. In these examples it will be appreciatedthat all temperatures are expressed in Centigrade, all melting andboiling points are uncorrected and all biological test data is expressedin terms of % activity of PGE₂ or administered at the same level (i.e.,PGE₂ = 100) unless otherwise noted.

The biological data given below was obtained using the following testprocedures:

Histamine-Induced Bronchoconstriction -- Guinea Pigs.

Bronchodilator activities were evaluated in conscious female Reed-Willetguinea pigs (200 to 250 g) fasted overnight according to the method ofVan Arman, Miller and O'Malley (1). At a pre-selected interval(pre-challenge interval) following oral or aerosol administration ofwater or the test drug in water, each animal was challenged withhistamine aerosol as follows: a 0.4% aqueous solution of histamine wasplaced in a Vaponephrine Standard Nebulizer (Vaponephrine Company,Edison, New Jersey) and sprayed under an air pressure of 6 lb/in² into aclosed 8 × 8 × 12 inch transparent plastic container for 1 min.Immediately thereafter, the guinea pig was placed in the container. Therespiratory status (a reflection of bronchoconstriction) of the guineapig after 1 min in the container was scored as follows: 0, normalbreathing; 1, slightly deepened breathing; 2, labored breathing; 3,severely labored breathing and ataxia; 4, unconsciousness. The scoresfor a control group and a test group (8 animals/group) were summed andcompared and the difference expressed as percent protection. (1)

Dog Blood Pressue

Mongrel dogs were anesthetized with sodium pentobarbitol, 30 mg/kg/i.v.Femoral artery blood pressure was measured with a mercury manometer andrecorded on smoked paper and heart rate was determined fromelectrocardiograms recorded from subcutaneous electrodes. Drugs weregiven through a cannula in a femoral vein.

Isolated Gastrointestinal and Reproductive Tissue

All measurements were made in a 2 ml tissue bath using a Phipps-BirdLinear Motion Transducer model ST-2. Tissues were allowed to respond toa stable maximum, at which point they were washed and allowed to returnto baseline condition. All determinations are an average of at leastthree individual tissues at each reported dose. Data for analogs werecompared to the dose response obtained for a natural PG in a giventissue. For purposes of potency comparisons, a standard dose of naturalPG was selected; and all responses were calculated as a percentage ofits response. Additional data were recorded as minimum effective dose(MED) and a consistently effective dose (CED) to establish compounddetection levels for each tissue. A standard equivalent dose (SED) wasdetermined. This value was defined as the amount of compound (ng/ml)which yielded a response that was equivalent to the tissue's response toa given dose of standard PG.

Guinea Pig Ileum:

The ileum was dissected from 200-300 g male guinea pigs sacrificed bycervical dislocation. The tissue was suspended in 2 ml Tyrode solution(2) at 37° C. PGE₂ (30 ng/ml and/or PGF₂.sub.α (30 ng/ml) were used toestablish tissue activity.

Guinea Pig Uterus (3):

Nulliparous females (300-L. J. g) which were not in estrus weresacrificed by cervical dislocation. The dissected uteri were incubatedin 2 ml of a modified Krebs solution (12) at 37°C. Uterine activity wasestablished using PGE₂ (1.0 ng/ml) and/or PGF₂.sub.α (10 ng/ml).

EXAMPLE 1 Dimethyl 2-Oxo-3-(2-thienyl)propylphosphonate (2a)

A solution of 37.2 g (0.3 mole) dimethyl methylphosphonate (Aldrich) in400 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogenatmosphere. To the stirred phosphonate solution was added 194 ml of 1.6M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwiseover a period of 18 minutes at such a rate that the reaction temperaturenever rose above -65°. After an additional 5 minutes stirring at -78°,23.4 g (0.15 mole) methyl 2-(2-thienyl)acetate was added dropwise at arate that kept the reaction temperature less than -70° (20 minutes).After 3.5 hours at -78° the reaction mixture was allowed to warm toambient temperature, neutralized with 6 ml acetic acid and rotaryevaporated to a white gel. The gelatinous material was taken up in 75 mlwater, the aqueous phase extracted with 100 ml portions of chloroform(3x) the combined organic extracts were backwashed (50 ml H₂ O), dried(MgSO₄), and concentrated (water aspirator) to a crude residue anddistilled, b.p. 150-52° (<0.5 mm) to give 4.8 g dimethyl2-oxo-3-(2-thienyl)propylphosphonate (2a).

The nmr spectrum (CDCl₃ (J showed a doublet centered at 3.7δ J = 11.0cps, 6H) for ##EQU3## a singlet at 4.12δ (2H) for Ar-CH₂ --CO--, adoublet centered at 3.16δ (J = 22 cps, 2H) ##EQU4## and a multiplet at6.8-7.3δ (3H) for the thienyl protons. In the same manner thecorresponding 3-thienyl compound was prepared. NMR data 3.65δ (J = 11cps), 3.1δ (J = 24 cps).

EXAMPLE 22-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-4-(2-thienyl)trans-1-buten-1-yl)-cyclopent-1α-yl]aceticacid, γ-lactone (3a)

Dimethyl 2-oxo-3-(2-thienyl)propylphosphonate (2a) (6.4 g, 25.7 mmole)in 300 ml. anhydrous ether was treated with 7.7 ml. (18 mmole) 2.34 Mn-butyllithium in n-hexane (Alfa Inorganics, Inc.) in a dry nitrogenatmosphere at room temperature. After 5 min. of stirring, an additional300 ml. of anhydrous ether was added, followed by 6.0 g. (17 mmole)2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-formylcyclopent-1.alpha.-yl]aceticacid, γ-lactone in one portion and 50 ml. anhydrous ether. After 35minutes, the reaction mixture was quenched with 5 ml. glacial aceticacid and washed with 100 ml. saturated brine (1x), dried (MgSO₄) andevaporated to yield 3.28 g.2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-y1]aceticacid, γ-lactone (3a) as an oil after column chromatography (silica gel,Baker, 60- 200 mesh).

The ir spectrum (CHCl₃) of the product exhibited adsorbtion bands at1770 cm.sup.⁻¹ (strong), 1705 cm.sup.⁻¹ (strong), 1675 cm.sup.⁻¹(medium) and 1625 cm.sup.⁻¹ (medium) attributable to the carbonyl groupsand at 970 cm.sup.⁻¹ for the trans double bond. The nmr spectrum (CDCl₃)exhibited a doublet centered at 6.27 (1H, J-16 cps) for the olefinicproton, a singlet at 4.01 (2H) for Ar--CH₂ --C, and multiplets at4.90-5.50 (2H) and 2.05-3.20 (6H) for the remainder of the protons. Inthe same manner the corresponding 3-thienyl compound was prepared havingIR bands at 1715, 1775, 1630, 1670 and 970 cm.sup.⁻¹.

The product (3a) may also be converted to 15-loweralkyl-16-(2-thienyl)-ω-tetranorprostaglandins of the A, E or F series bythe procedures of examples 4-12 and 14-20.

13,14 Dihydro-15-lower alkyl-16(2-thienyl)-ω-tetranorprostaglandins ofthe A, E or F series may be obtained from (3a) via the procedures ofexamples 4-12, 14, and 19-20.

EXAMPLE 3 2-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl]acetic acid, γ-lactone (4a) and2-]3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (5a).

To a solution of 4.7 g. (10 mmole)2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (3a) in 30 ml. dry 1,2-dimethoxyethane in a dry nitrogenatmosphere at ambient temperature was added dropwise 10 ml. of a 0.5 Mzinc borohydride solution. After stirring at room temperature for 1hour, a saturated sodium bitartrate solution was added dropwise untilhydrogen evolution ceased. The reaction mixture was allowed to stir for5 minutes at which time 200 ml. dry methylene chloride was added. Afterdrying (MgSO₄) and concentrating (water aspirator), the resultantsemisolid was purified by column chromatography on silica gel (Baker"Analyzed" Reagent 60-200 mesh) using ether as eluent. After elution ofless polar impurities, a fraction containing 710 mg.2-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (4a), a 50 mg. fraction of mixed 4 and 5 and finally afraction (862 mg.) of2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-4-(2-thienyl)-trans-1-buten-yl)cyclopent-1α-yl]aceticacid, γ-lactone (5a).

The ir spectrum (CHCl₃) of 4 had strong carbonyl adsorbtions at 1770 and1710 cm.sup.⁻¹ and an adsorbtion at 965 cm.sup.⁻¹ for the trans doublebond. In the same manner the corresponding 3-thienyl compound wasprepared from the appropriate starting material. α-Hydroxyl epimer (lesspolar on TLC) m.p. 101.5°-102.5°C. β-Hydroxyl epimer (more polar on TLC)m.p. 109°-111°C. The compounds were crysallized from EtAc-pentane.

EXAMPLE 42-[3α,5α-Dihydroxy-2β-(3α-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (6a):

A heterogeneous mixture of 1.35 g (2.85 mmole) of2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (4a), 13 ml. of absolute methanol and 394 mg of finelypowdered, anhydrous potassium carbonate was stirred at room temperaturefor 1 hour, then cooled to 0°. To the cooled solution was added 5.6 mlof 1. ON aqueous hydrochloric acid. After stirring at 0° for anadditional 10 minutes, 15 ml. of water was added with concomitantformation of methyl p-phenylbenzoate which was collected by filtration.The filtrate was saturated with solid sodium chloride, extracted withethyl acetate (4 × 20 ml.), the combined organic extracts were washedwith saturated sodium bicarbonate (10 ml.), dried (MgSO₄) andconcentrated to give 738 mg of viscous, oily2-[3α,5α-dihydroxy-2β-(3α-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (6a).

The ir spectrum (CHCl₃) exhibited a strong adsorption at 1755 cm.sup.⁻¹for the lactone carbonyl and medium adsorption at 965 cm.sup.⁻¹ for thetrans-double bond. In the same manner the corresponding 3-thienylcompounds were prepared. 15-αOH IR 1774, 970 cm.sup.⁻¹ 15-βOH IR 1775,970 cm.sup.⁻¹.

EXAMPLE 52-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-(tetrahydropyran-2-yloxy)-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (7a)

To a solution of 738 mg (2.5 mmole)2-[3α,5α-dihydroxy-2β-(3α-hydroxy-4-(2-thienyl)-trans-1-buten-yl)cyclopent-1α-yl]aceticacid, γ-lactone (6a) in 5 ml. anhydrous methylene chloride and 0.5 ml.of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere was added 7 mgp-toluenesulfonic acid, monohydrate. After stirring for 15 minutes, thereaction mixture was combined with 100 ml. ether, the ether solutionwashed with saturated sodium bicarbonate (1 × 15 ml) then saturatedbrine (1 × 25 ml.), dried (MgSO₄) and concentrated to yield 1.2 g(>100%) crude 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-(tetrahydropyran-2-yloxy)-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (7a).

The ir (CHCl₃) spectrum displayed a medium absorbtion at 970 cm.sup.⁻¹for the trans-double bond and at 1772 cm.sup.⁻¹ for the lactonecarbonyl.

In the same manner the corresponding 3-thienyl compounds were prepared.

    ______________________________________                                        15α-OTHP  IR 1770, 970 cm.sup..sup.-1.                                  15β-OTHP   IR 1770, 970 cm.sup..sup.-1.                                  ______________________________________                                    

EXAMPLE 62-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-4-phenyl-trans-1-buten-1-yl)cyclopent-1α-yl]acetaldehyde,γ-hemiacetal (8a):

A solution of 1.2 g (2.5 mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1.alpha.-yl]acetic acid, γ-lactone (7a) in 25 ml dry toluene was cooled to -78° in adry nitrogen atmosphere. To this cooled solution was added 3.4 ml of 0.8M diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise atsuch a rate so that the internal temperature never rose above -65° (15minutes). Afer an additional 45 minutes of stirring at -78°, anhydrousmethanol was added until gas evolution ceased and the reaction mixturewas allowed to warm to room temperature. The reaction mixture wascombined with 150 ml ether, washed with 50% sodium potassium tartratesolution (4 × 20 ml), dried (Na₂ SO₄) and concentrated to a quantitativeyield of oily 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1-yl]acetaldehyde,γ-hemiacetal (8a). The ir spectrum displayed a broad absorption at 3400cm.sup.⁻¹ for the hydroxyl group. In the same manner the corresponding3-thienyl compounds were prepared.

    ______________________________________                                        15α-OTHP  IR:  970 cm.sup..sup.-1.                                      15β-OTHP   IR:  970 cm.sup..sup.-1.                                      ______________________________________                                    

EXAMPLE 79α-Hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thenyl)-cis-5-trans-13-ω-tetranor-prostadienoicacid (9a)

To a solution of 2.6 g (6 mmole) (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 ml. drydimethyl sulfoxide was added 5.7 ml. (11.4 mmole) of a 2.2M solution ofsodium methylsulfinylmethide in dimethyl sulfoxide. To this red ylidesolution was added dropwise a solution of 1.03 g. (2.2 mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]acetaldehyde, γ-hemiacetal (8a) in 5.0 ml. dry dimethylsulfoxide over a period of 20 minutes. After an additional 2 hoursstirring at room temperature, the reaction mixture was poured into icewater. The basic aqueous solution was washed twice with ethyl acetate(20 ml.) and acidified to pH˜3 with 10% aqueous hydrochloric acid. Theacidic solution was extracted with ethyl acetate (3 × 20 ml.) and thecombined organic extracts washed once with water (10 ml.), dried (MgSO₄)and evaporated to a solid residue. This solid residue was trituratedwith ethyl acetate and the filtrate concentrated to yield 1.02 g. of9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid 9a. The ir spectrum displayed a strong band at 1700 cm.sup.⁻¹ alongwith absorptions between 2800 to 2600 cm.sup.⁻¹ for the carboxyl group.

In the same manner the corresponding 3-thienyl compounds were prepared.

    ______________________________________                                        15α-OTHP  IR:  1710, 970 cm.sup..sup.-1.                                15β-OTHP   IR:  1710, 970 cm.sup..sup.-1.                                ______________________________________                                    

EXAMPLE 89-Oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-ω-tetranor-prostadienoicacid (10a)

To a solution cooled to -10° under nitrogen of 1.02 g (1.86 mmole)9α-hydroxy-11α,15α-bis(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-ω-tetranor-prostadienoicacid (9a) in 18 ml. reagent grade acetone was added dropwise to 0.82 ml.(2.04 mmole) of Jones' reagent. After 20 minutes at -10°, 0.260 ml.2-propanol was added and the reaction mixture was allowed to stir anadditional 5 minutes at which time it was combined with 75 ml. ethylacetate, washed with water (3 × 10 ml.), dried (MgSO₄) and concentratedto give 952 mg. of9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-ω-tetranor-prostadienoicacid (10α), which was chromatographed on silica gel using ethyl acetateas eluent to afford 760 mg of pure 10a. In the same manner both thecorresponding 3-thienyl compounds epimeric at C₁₅ were prepared.

EXAMPLE 99-Oxo-11α,15α-dhydroxy-16-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid (11a)

A solution of 760 mg. (1.39 mmole)9-oxo-11α,15α-bis-tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid (10a) in 3.0 ml. of a 65:35 mixture of glacial acetic acid:waterwas stirred under nitrogen at 25° for 18 hour then was concentrated byrotary evaporation. The resultant crude oil was purified by columnchromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) usingethyl acetate as eluent. After elution of less polar impurities the oily9-oxo-11α,15α-dihydroxy-16-phenyl-cis-5-trans-13-ω-tetranor-prostadienoicacid (11a) weighing 369 mg. was collected.

IR displayed carbonyl absorbtions at 1730 and 1705 cm.sup.⁻¹, and a weakband at 972 cm.sup.⁻¹ for the 13,14-trans double bond.

The product of this example (11a) can be converted to16-(2-thienyl)-ω-tetranorprostaglandins E₁ E₀, A₂, A₁ and A₀ via theprocedures of examples 12, 19 and 20. In the same manner thecorresponding 3-thienyl compounds were prepared.

    ______________________________________                                        15α-OH                                                                             IR:  1715, 1740, 970 cm.sup..sup.-1.                               15β-OH                                                                              IR:  1715, 1740, 970 cm.sup..sup.-1.                               ______________________________________                                    

Biological activity: Guinea pig uterus 2-4; bronchodilator test 63; dogblood pressure 200.

EXAMPLE 10 9α,11α,15α-Trihydroxy-16-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid (12a)

A mixture of 0.76 g. of9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid (9a) in 5 ml. of a 65:35 mixture of acetic acid: water is stirredunder nitrogen at room temperature overnight, then is concentrated underreduced pressure to a viscous oil. The crude product is purified bycolumn chromatography on Mallinckrodt CC-4 silica gel using ethylacetate as eluent. After elution of less polar impurities, the desired9α,11α,16α-trihydroxy-16-(2-thienyl)-cis-5-trans-13-.omega.-tetranorprostadienoicacid (12a) is obtained as a viscous, colorless oil weighting 51 mg.

The product obtained above (12a) may be converted to16-(2-thienyl)-ω-tetranorprostaglandin F₁.sub.α via the process ofExample 20. 12a may also be converted to16-(2-thienyl)-ω-tetranorprostaglandin F₀.sub.α, via the process ofExample 19.

EXAMPLE 11 2-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-3β-methyl-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (13a) and2-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-3α-methyl-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid γ-lactone (14a)

To a solution of 3190 mg. (6.2 mmole)2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (3a) in 26 ml. anhydrous etherand 20 ml. of tetrahydrofuran (distilled from LAH) in a dry nigrogenatmosphere at -78° is added dropwise 6.8 ml. of (0.92M) methyllithium inether (Alfa). After stirring at -78° for 15 minutes the reaction isquenched by the dropwise addition of glacial acetic acid until the pH ofthe reaction is approximately 7. The mixture is then diluted withmethylene chloride and the diluted organic solution is washed with water(1x) and with saturated brine (1x), is dried (anhydrous magnesiumsulfate), and is concentrated to afford the epimeric alcohols.

The crude product is purified by column chromatography on silica gel toprovide the2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-3β-methyl-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (13a), and2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-3α-methyl-4-(2-thienyl)-trans-1-buten-yl)cyclopent-1α-yl]aceticacid, γ-lactone (14a).

This material (14a) may be converted to the 15βmethyl-16-2(thienyl)-ω-tetranorprostaglandins of the A, E, and F seriesby the procedures outlined in Examples 4-10 and 12-20.

Other lower alkyl derivatives of the type (14a) may be prepared bysubstituting the appropriate alkyl lithium derivative for methyl lithiumin the above procedure. These derivatives are suitable for conversion to15 lower-alkyl 16-2(thienyl)-ω-tetranorprostaglandins of the A, E, and Fseries through the sequences of Example 3-10 and 12-20.

EXAMPLE 12 9-oxo-15α-hydroxy-16-2(thienyl)-cis-5-Δ¹⁰,11-trans-13-ω-tetranorprostatrienoic acid (15a)

A solution of 55 mg. of9-oxo-11α,15α-dihydroxy-16-2(thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid (11a) in 10 ml. dry methylene chloride and 10 ml. formic acid isstirred at room temperature for 5 hours. The reaction mixture is dilutedwith 50 ml. toluene and evaporated to yield (after chromatography)9-oxo-11α-hydroxy-16-2(thienyl)-cis-5-Δ¹⁰,11-trans-13-ω-tetranorprostarienoic acid (15a).

In the same way 16-substituted-ω-pentanorprostaglandins of the A₁, A₀and 13,14 dihydro A₂ series may be prepared from16-substituted-ω-pentanorprostaglandins of the E₁, E₀ and 13,14-dihydroseries respectively.

EXAMPLE 13

The procedure of example 3 in which sodium borohydride is substitutedfor zinc borohydride may be used to produce 19a. 19a may then beconverted to 24a via the procedure of example 4, which is furtherconverted to 13,14 dihydro-16-2(thienyl)-ω-tetranorprostaglandins of theA, E or F series by the procedures of examples 15- 18, 10, and 12.

EXAMPLE 142-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-4-(2-thienyl)but-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (24a)

A stirred heterogeneous solution of 1.7 g. (3.4 mmole)2-[5α-hydroxy-3α(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-4-2(thienyl)-trans-1-buten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (7d) and 300 mg. 5% rhodium on alumina in 35 ml. atabsolute methanol is hydrogenated for 90 minutes. The reaction mixtureis filtered through filter aid and concentrated (in vacuo) to yield2-[5α-hydroxy-3α(tetrahydropyran-2-yloxy)-2β-(3.alpha.-[tetrahydropyran-2-yloxy]-4-2(thienyl)but-1-yl)cyclopentan-1α-yl]aceticacid, γ-lactone (24a).

EXAMPLE 152[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-4-(2-thienyl)but-1-yl)cyclopent-1α-yl]acetaldehyde, γ-hemiacetal (25a)

A solution of 1600 mg. (3.2 mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-4-2(thienyl)but-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (24a) in 15 ml. drytoluene is cooled to -78° in a dry nitrogen atmosphere. To this cooledsolution is added 5.0 ml. of 20% diisobutylaluminum hydride in n-hexane(Alfa Inorganics) dropwise at such a rate so that internal temperaturenever rises above -65° (3 minutes). After an additional 30 minutes ofstirring at -78°, anhydrous methanol is added until gas evolution ceasesand the reaction mixture is allowed to warm to room temperature. Thereaction mixture is combined with 150 ml. ether, washed with 50% sodiumpotassium tartrate solution (1 × 50 ml.), dried (Na₂ SO₄) concentrated,and chromatographed to yield 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-4-(2-thienyl)but-1-yl)cyclopent-1-yl]acetalehyde,γ-hemiacetal (25a).

EXAMPLE 169α-Hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-ω-tetranorprostenoicacid (22a)

To a solution of 5150 mg. (11.6 mmole)(4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogenatmosphere in 10.1 ml. dry dimethyl sulfoxide is added 10.8 ml. (21.1mmole) of a 1.96M solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution is added dropwise a solution of1300 mg. (2.6 mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-4-(2-thienyl)-but-1-yl)cyclopent-1α-yl]acetaldehyde,γ-hemiacetal (25a) in 7.0 ml. dry dimethyl sulfoxide over a period of 20minutes. After an additional 2 hours stirring at room temperature, thereaction mixture is poured into ice water. The basic aqueous solution isacidified to pH˜3 with 10% aqueous hydrochloric acid. The acid solutionis extracted with ethyl acetate (3 × 100 ml.) and the combined organicextracts washed once with water (50 ml.), dried (MgSO₄) and evaporatedto a solid residue. This solid residue is triturated with ethyl acetateand filtered. The filtrate is purified by column chromatography onsilica gel to provide9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-ω-tetranorprostenoic(22a) acid is collected.

The product obtained above (22a) may be converted to16-(2-thienyl)-ω-tetranor-13,14-dihydro PGF₂.sub.α via the process ofExample 10.

EXAMPLE 179-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-ω-tetranorprostenoicacid (26a)

To a solution cooled to -10° under nitrogen of 950 mg. (1.68 mmole)9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-ω-tetranorprostenoicacid (22a) in 15 ml. reagent grade acetone is added dropwise 0.75 ml. (2mmole) of Jones ' reagent. After 20 minutes at -10°, 0.75 ml. 2-propanolis added and the reaction mixture is allowed to stir an additional 5minutes at which time it is combined with 100 ml. ethyl acetate, washedwith water (3 × 25 ml.), dried (MgSO₄) and concentrated to give of9-oxo-11α,15α-bis-(tetrahydroyran-2-yloxy)-16-(2-thienyl)-cis-5-ω-tetranorprostenoicacid (26a).

EXAMPLE 189-oxo-11α,15α-dihydroxy-16-(2-thienyl)-cis-5-ω-tetranorprostenoic acid(27a)

A solution of 800 mg.9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-ω-tetranorprostenoicacid (26a) in 7.0 ml. of a 65:35 mixture of glacial acetic acid:water isstirred under nitrogen at 25° for 20 hours and then is concentrated byrotary evaporation. The resultant crude oil is purified by columnchromatography to provide the9-oxo-11α,15α-dihydroxy-16-(2-thienyl)-cis-5-ω-tetranorprostenoic acid(27a).

The product of this example (27a) may be converted to the16-(2-thienyl)-cis-5-ω-tetranorprostaglandin A₂ by the procedure ofExample 12.

EXAMPLE 19 9-oxo-11α,15α-dihydroxy-16-(2-thienyl)-ω-tetranorprostanoicacid (28a)

A heterogeneous solution of 37 mg. (.089 mmole)9-oxo-11α,15α-dihydroxy-16-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid (11d) and 37 mg. of 5% rhodium on alumina in 3 ml. absolutemethanol is hydrogenated (1 atm) at 0° for 2 hours. The reaction mixtureis filtered and evaporated to yield9-oxo-11α,15α-dihydroxy-16-(2-thienyl)-ω-tetranorprostanoic acid (28a).

EXAMPLE 209-oxo-11α,15α-dihydroxy-16-(2-thienyl)-trans-13-ω-tetranorprostenoicacid (29a)

A solution of 50 mg. 9-oxo-11α,15α-dihydroxy-16-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoic acid (11a) in 5 ml. of dry tetrahydrofuran istreated with 448 mg. (3.6 mmole) dimethyl isopropyl chlorosilane and 1.0g. (3.6 mmole) 1,1,3,3-tetramethyl-1,3-diisopropyldisilazane at 25° for48 hours, evaporated to a residue. The crude residue is then taken up in6 ml. of a 3:2 mixture of acetone:benzene and 30 mg. of tris(triphenylphosphine) rhodium chloride is added and the resulant solutionis hydrogenated for 7 hours at 20-30 psi. The solution is evaporated andthe residue dissolved in 2.0 ml. of ethanol then poured into 5 ml. of0.2M Na₂ HPO₄ buffer. The mixture is extracted with ether, then theaqueous layer is acidified to pH 3 with 10% hydrochloric acid, isstirred for 5 minutes then is extracted with ethyl acetate. The combinedorganic extracts are washed with water (2 × 10 ml.), dried (MgSO₄) andevaporated to yield 9-oxo-11α,15α-dihydroxy-16-(2-thienyl)-trans-13-ω-tetranorprostenoic acid (29a) after silica gel chromatography.

EXAMPLE 212-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl]acetaldehyde,γ-hemiacetal

To a stirred solution, cooled to -78°, of the2-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl]aceticacid, γ-lactone in 78.8 ml. of toluene was added 13.4 ml. (10.8 mmoles)of a 0.805M solution of diisobutyl-aluminum hydride in hexane dropwise.The solution was stirred in the cold under nitrogen for 1.0 hour thenwas quenched by the dropwise addition of methanol until gas evolutionceased. The quenched mixture was warmed to room temperature, was dilutedwith ether (79 ml.), was washed with 50% sodium potassium tartrate (3x)and saturated brine (1x), was dried (anhydrous magnesium sulfate), andwas concentrated to afford the crude, colorless oily2-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl]acetaldehyde,γ-hemiacetal weighing 3.15 g. (92.0% yield). The ir, nmr, and massspectra of the oil were consistent with the assigned structure.

    ______________________________________                                        Spectra:                                                                      ir (CHCl.sub.3):                                                               no carbonyl                                                                  nmr (CDCl.sub.3): -                                                             7.31        δ                                                                             singlet  5H    aromatic                                   5.32-5.75                                                                       δ     broad 1H       OH                                                             singlet                                                         4.50                                                                            δ     singlet                                                                             2H       φCH.sub.2 --O                                4.45-4.98                                                                       δ     multiplet                                                                           2H       O--CH--O                                         3.44                                                                            δ     quartet                                                                             2H       --CH.sub.2 O--BZ                                               J = 9 cps                                                                     J = 4 cps                                                       1.20-4.40                                                                       δ     multiplets                                                                          16H      remaining protons                                ______________________________________                                    

EXAMPLE 227-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl]-cis-5-heptenoicacid

To a solution of 4.96 g. (11.2 mmoles of(4-carboxy-n-butyl)triphenylphosphonium bromide in 8.85 ml. of dimethylsulfoxide was added dropwise 9.73 ml. (21.2 mmoles) of a 2.18 M solutionof sodium methylsulfinylmethide in dimethyl sulfoxide. To the resultantred ylide solution was added dropwise over a period of 1.0 hour asolution of 1.57 g. (4.50 mmoles) of the crude hemiacetal prepared inExample 21 in 13.7 ml. of dimethyl sulfoxide. After being stirred for anadditional 45 minutes the reaction was poured onto ice-water. The basicaqueous solution was extracted with a 2:1 mixture of ethyl acetate:ether(2 × 60 ml.) was then covered with ethyl acetate, and was acidified with1.0 N hydrochloric acid to pH˜3. The aqueous layer was extracted furtherwith ethyl acetate; the combined ethyl acetate extracts were washed withwater, were dried (anhydrous magnesium sulfate), and were concentratedto a viscous yellow oil. The crude oil was purified by chromatography on30 g. of silica gel using ethyl acetate as eluent. After elution of highR_(f) impurities the desired 7-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl]-cis-5-heptenoicacid was collected weighing 1.75 g. (90.0% yield).

    __________________________________________________________________________    Spectra:                                                                      ir (CHCl.sub.3):                                                                5.82 μ    acid    carbonyl                                               nmr (CDCl.sub.3):                                                             7.30         δ                                                                         singlet 5H   aromatic                                          6.44-7.00    δ                                                                         broad singlet                                                                         2H   --OH                                              5.28-5.58    δ                                                                         multiplet                                                                             2H   olefinic                                          4.62-4.79    δ                                                                         broad singlet                                                                         1H   --O--CH--O                                        4.51         δ                                                                         singlet 2H   φ--CH.sub.2 --O                               3.23-4.38    δ                                                                         multiplets                                                                            8H   --CH--O &                                                                     --CH--O                                           1.22-2.53    δ                                                                         multiplets                                                                            16H  remaining                                                                     protons                                           Optical Rotation:                                                             [a].sub.D.sup.25 =+15.1°(C 9.94, HCCl.sub.3).                          __________________________________________________________________________

EXAMPLE 23 Methyl7-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl]-cis-5-heptenoate

A solution of 1.75 g. (4.06 mmoles) of the chromatographed acid preparedin Example 22 in 17.5 ml. of anhydrous ether was titrated at roomtemperature with an ethereal diazomethane solution until the yellowcolor persisted for 5 minutes. The reaction was then decolorized by thedropwise addition of glacial acetic acid. The ethereal solution was thenwashed with saturated sodium bicarbonate (1x) and saturated brine (1x),was dried (anhydrous magnesium sulfate), and was concentrated to affordthe faintly-yellow, oil methyl7-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl]-cis-5-heptenoateweighing 1.80 g. (99.0% yield).

    __________________________________________________________________________    Spectra:                                                                      ir (CHCl.sub.3):                                                                5.77 μ    Ester carbonyl                                                 nmr (CDCl.sub.3):                                                             7.31         δ                                                                         singlet 5H  aromatic                                           5.62-5.30    δ                                                                         multiplet                                                                             2H  olefinic                                           4.81-4.63    δ                                                                         broad singlet                                                                         1H  --O--CH--O                                         4.53         δ                                                                         singlet 2H  φ--CH.sub.2 --O                                3.66         δ                                                                         singlet 3H  --O--CH.sub.3                                      4.42-3.67    δ                                                                         multiplets                                                                            9H  --CH.sub.2 --O &                                                              --CH--O                                            2.55-1.36    δ                                                                         multiplets                                                                            12H remaining                                                                     protons                                            __________________________________________________________________________

EXAMPLE 24 Methyl7-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-acetoxycyclopent-1α-yl]-cis-5-heptenoate

A mixture of 1.58 g. (3.54 mmoles) of the crude hydroxyester prepared inExample 23, 5.0 ml. of pyridine and 0.736 ml. (7.78 mmoles) of aceticanhydride was stirred under nitrogen at 50° overnight. The mixture wascooled to room temperature and was diluted with ether (75 ml.). Theetheral solution was washed with water (1x) and with saturated coppersulfate (3x), was dried (anhydrous magnesium sulfate), and wasconcentrated to afford the colorless, oily methyl7-[2β-benzyloxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-acetoxycyclopent-1α-yl]-cis-5-heptenoateweighing 1.61 g. (93.5% yield).

    __________________________________________________________________________    Spectra:                                                                      ir (CHCl.sub.3):                                                               1750 cm.sup..sup.-1                                                                         ester carbonyls                                                nmr (CDCl.sub.3):                                                             7.30         δ                                                                         singlet  5H  aromatic                                          5.51-5.23    δ                                                                         multiplet                                                                              2H  olefinic                                          5.22-4.91    δ                                                                         multiplet                                                                              1H  --CH--O--Ac                                       4.52         δ                                                                         singlet  2H  φ--CH.sub.2 --O--                             3.63         δ                                                                         singlet  3H  --O--CH.sub.3                                     4.67-3.20    δ                                                                         multiplets                                                                             8H  --O--CH &                                                                     --O--CH.sub.2                                                                 O                                                                             ∥                                        2.06         δ                                                                         singlet  3H  --CCH.sub.3                                       2.55-1.22    δ                                                                         multiplets                                                                             16H remaining                                                                     protons                                           __________________________________________________________________________

EXAMPLE 25 Methyl7-[2β-hydroxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-acetoxycyclopent-1α-yl]heptanoate

A heterogeneous mixture of 1.53 g. (3.14 mmoles) of the crude acetoxyester prepared in Example 24, 305 mg. of 5% palladium on carbon, and15.3 ml. of a 20:1 mixture of absolute ethanol:glacial acetic acid wasstirred at room temperature under one atmosphere of hydrogen for 48hours. The mixture was then filtered through Celite 545 and the filtratewas concentrated to afford the colorless, oily methyl7-[2β-hydroxymethyl-3α-(tetrahydropyran-2-yloxy)-5α-acetoxycyclopent-1α-yl]heptanoateweighing 1.10 g. (87.5% yield).

    __________________________________________________________________________    Spectra:                                                                      ir (CHCl.sub.3):                                                               1750 cm.sup..sup.-1                                                                         ester carbonyls                                                nmr (CDCl.sub.3):                                                             5.23-4.92    δ                                                                         multiplet                                                                              1H  --CH--OAc                                         4.83-4.46    δ                                                                         multiplet                                                                              1H  --O--CH--O                                        3.65         δ                                                                         singlet  3H  --O--CH.sub.3                                     4.32-3.18    δ                                                                         multiplets                                                                             7H  --O--CH &                                                                     --O--CH.sub.2 --                                  3.06-2.70    δ                                                                         broad singlet                                                                          3H  O                                                                             ∥                                                                    --CCH.sub.3                                       2.58-1.00    δ                                                                         multiplets                                                                             20H remaining                                                                     protons                                           __________________________________________________________________________

EXAMPLE 26 Methyl7-[2β-formyl-3α-(tetrahydropyran-2-yloxy)-5α-acetoxycyclopent-1α-yl]heptanoate

To a mechanically stirred solution of 3.37 ml. (41.7 mmoles) of pyridinein 50 ml. of methylene chloride cooled to 10° to 15° under nitrogen wasadded portionwise over a period of 30 minutes 1.89 g. (18.9 mmoles) ofchromium trioxide. The dark burgundy solution was then let warm to roomtemperature then was cooled to 0°. To the cold solution was added asolution of 0.947 g. (2.37 mmole) of the crude alcohol prepared inExample 25 in 7.0 ml of methylene chloride with the concomitantformation of a dense black precipitate. The suspension was stirred inthe cold for 15 minutes then 7.21 g. (52.2 mmoles) of finely groundsodium bisulfate monohydrate was added. After being stirred for 10minutes 6.25 g. (52.2 mmoles) of anhydrous magnesium sulfte was added.After being stirred for 5 minutes the dark suspension was filteredthrough a pad of Celite, was washed with methylene chloride, then wasconcentrated by rotary evaporation (bath <10° ) to afford the crude,dark brown, oily methyl7-[2β-formyl-3α-(tetrahydropyran-2-yloxy)-5α-acetoxycyclopent-1α-yl]heptanoatewhich was used without purification.

EXAMPLE 27 Methyl 9α-acetoxy-11α-(tetrahydropyran-2-yloxy)-15-oxo-trans-13-16-(2-thienyl)-ω-tetranorprostenoate

To a suspension of 137 mg. (3.25 mmoles) of a 57.0% dispersion of sodiumhydride in mineral oil in 30 ml. of tetrahydrofuran was added 885 mg.(3.55 mmoles) of dimethyl-2-oxo-3-(2-thienyl)propylphosphonate. Themixture was stirred at room temperature for 0.5 hour under nitrogen. Tothis suspension was added a solution of 1.30 g. (3.25 mmoles) of thecrude aldehyde prepared in Example 25 in 10 ml. of tetrahydrofuran. Theresultant slightly turbid, brown solution was stirred at roomtemperature for 2.0 hours under nitrogen. The reaction was then quenchedby the addition of glacial acid to pH˜5 and was concentrated by rotaryevaporation. The crude product was purified by column chromatography onsilica gel using mixture of benzene:ether as eluents to afford thedesired methyl9α-acetoxy-11α-(tetrahydropyran-2-yloxy)-15-oxo-trans-13-16-(3-thienyl)-ω-tetranorprostenoateas a viscous yellow oil weighing 941 mg.

EXAMPLE 28 Methyl9α-acetoxy-11α-(tetrahydropyran-2-yloxy)-15-hydroxy-trans-13-16-(2-thienyl)-ω-tetranorprostenoate

To a solution, cooled to -78°, of 0.941 g. (1.81 mmoles) of the enoneprepared in Example 27 in 25 ml. of tetrahydrofuran was added dropwise1.81 ml. (1.81 mmoles) of a 1:0M lithium triethylborohydride solution intetrahydrofuran. After being stirred in the cold under nitrogen for 25minutes the reaction was quenched by the addition of 1 ml. of a 9:1mixture of water:acetic acid. The quenched heterogeneous solution waswarmed to room temperature and concentrated. The residue was dissolvedin ethyl acetate, the organic layer was washed with water and saturatedsodium bicarbonate, was dried (MgSO₄), and concentrated. The crudeproduct was purified by silica gel chromatography using mixtures ofbenzene:ether as eluents which afforded methyl9α-acetoxy-11α-(tetrahydropyran-2-yloxy)-15β-hydroxy-trans-13-16(2-thienyl)-ω-tetranorprostenoate weighing 257 mg then after mixed fractions methyl9α-acetoxy-11α-(tetrahydropyran-2-yloxy)-15α-hydroxy-trans-13-16-(2-thienyl)-ω-tetranorprostenoateweighing 455 mg.

EXAMPLE 29Methyl-9α-acetoxy-11α,15β-dihydroxy-trans-13-16-(2-thienyl)-ω-tetranorprostenoateand methyl 9α-acetoxy-11α,15α-dhydroxy-trans-13-16-(2-thienyl)-ω-tetranorprostenoate.

A solution of 1.60 g. (2.16 mmoles) of the crude THP ether prepared inExample 28 in 10.7 ml. of a 65:35 mixture of acetic acid:water isstirred at 40° ± 2° under nitrogen for 2.5 hours. The reaction mixtureis then concentrated to afford the crude epimeric diol mixture. Thecrude product is purified by column chromatography on silica gel toprovide the desiredmethyl-9α-acetoxy-11α,15β-dihydroxy-trans-13-16-(2-thienyl)-ω-tetranorprostenoateand the epimeric methyl9α-acetoxy-11α,15α-dihydroxy-trans-13-16-(2-thienyl)-.omega.-tetranorprostenoate.

EXAMPLE 30 Methyl9α-acetoxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(2-thienyl)-ω-tetranorprostenoate

A mixture of 0.413 g. (0.790 mmole) of the chromatographed more polarepimer of Example 28, 0.22 ml. (2.40 mmoles) of dihydropyran, 8 ml. ofmethylene chloride, and 1 crystal of p-toluenesulfonic acid monohydratewas stirred at room temperature under nitrogen for 30 minutes. Thereaction mixture was then diluted with ether, is washed with saturatedaqueous sodium bicarbonate, was dried (anhydrous magnesium sulfate), andwas concentrated to give the desired methyl9α-acetoxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(2-thienyl)-ω-tetranorprostenoateas a yellow oil weighing 517 mg. (> 100% yield).

EXAMPLE 319α,11α,15α-trihydroxy-trans-13-16-(2-thienyl)-ω-tetranorprostenoic acid

A mixture of 65 mg. (0.15 mmoles) of the chromatographed diol preparedin Example 29, 0.45 ml. (0.45 mmole) of 1.0 N aqueous sodium hydroxide,0.45 ml. of tetrahydrofuran, and 0.45 ml. of absolute methanol isstirred under nitrogen at room temperature for 1.5 hours. The solutionis then acidified by the addition of 0.45 ml. of 1.0 N aqueoushydrochloric acid (pH of acidified solution was ca. 5). The acidifiedsolution is extracted with ethyl acetate (4 × 2 ml.). The combinedextracts are dried (anhydrous magnesium sulfate) and concentrated toafford the desired9α,11α,15α-trihydroxy-trans-13-16-(2-thienyl)-ω-tetranorprostenoic acid.

EXAMPLE 329α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(2-thienyl)-ω-tetranorprostenoicacid

A homogeneous solution of 5.7 mg (0.790 mmole) of the crude bis-THPester prepared in Example 30, 2.37 ml (2.37 mmoles) of the 1.0N aqueoussodium hydroxide solution, 2.0 ml of methanol, and 2.5 ml oftetrahydrofuran was stirred under nitrogen for 2 hours. The reaction wasthen quenched by the addition of 2.37 ml of a 1.0N aqueous hydrochloricacid solution. The quenched solution was diluted with ethyl acetate. Theorganic layer was dried (anhydrous magnesium sulfate) and concentratedto afford the crude product. The crude product was purified by columnchromatography on Baker "Analyzed" silica gel (60-200 mesh) usingmixtures of benzene-ether as eluents to provide the9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(2-thienyl)-ω-tetranorprostenoicacid as a yellow oil weighing 414 mg (95.4% yield).

EXAMPLE 339-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy-13-trans-16-(2-thienyl)-ω-tetranorprostenoicacid

To a solution, cooled under nitrogen to -15° to -20° , of 414 mg (0.751mmole) of the chromatographed acid prepared in Example 32 in 8.0 ml ofacetone was added dropwise 0.310 ml (0.27 mmole) of Jones' reagent. Thereaction was stirred in the cold for 20 minutes then was quenched by theaddition of 0.31 ml of isopropanol. The quenched reaction was stirred inthe cold for 5 minutes then was diluted with ethyl acetate. The organicsolution was washed with water (2x) and saturated brine (1x), was dried(anhydrous magnesium sulfate), and was concentrated to afford thedesired9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-13-trans-16-(2-thienyl)-ω-tetranorprostenoicacid as a yellow oil weighing 367 mg (89.0% yield).

EXAMPLE 349-oxo-11α,15α-dihydroxy-13-trans-16-(2-thienyl)-ω-tetranorprostenoicacid

A homogeneous solution of 367 mg (0.670 mmole) of the crude THP ether ofExample 33 in 10 ml of a 65:35 mixture of acetic acid:water was stirredunder nitrogen at room temperature for 17.5 hours. The reaction wasconcentrated by rotary evaporation followed by oil pump. The crude brownproduct was purified by column chromatography on silica gel(Mallinckrodt CC-7) using mixtures of chloroform: ethyl acetate aseluents to provide the desired9-oxo-1α,15α-dihydroxy-13-trans-16-(2-thienyl)-ω-tetranorprostenoic acidas a crystalline solid weighing 144 mg (56.7% yield) and melting at63°-65° from ether: cyclohexane.

EXAMPLE 35 Dimethyl 2-Oxo-4-(2-thienyl)butylphosphonate (2b)

A solution of 11.6 g (94 mmoles) dimethyl methylphosphonate (Aldrich) in130 ml. dry tetrahydrofuran was cooled to -78° in a dry nitrogenatmosphere. To the stirred phosphonate solution was added 43 ml of 2.26M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwiseover a period of 18 minutes at such a rate that the reaction temperaturenever rose above -65°. After an additional 5 minutes stirring at -78°,8.0 g. (47 mmole) methyl 3-(2-thienyl)propionate was added dropwise at arate that kept the reaction temperature less than -70° (20 minutes).After 3.5 hours at -78°, the reaction mixture was allowed to warm toambient temperature, neutralized with 5 ml. acetic acid and rotaryevaporated to a white gel. The gelatinous material was taken up in 75ml. water, the aqueous phase extracted with 100 ml. portions ofchloroform (3x), the combined organic extracts were backwashed (50 cc H₂O), dried (MgSO₄), and concentrated (water aspirator) to a crude residueand distilled, b.p. 156° (10.2mm) to give 9.7 g. dimethyl2-oxo-4-(2-thienyl)butylphosphonate.

The nmr spectrum (CDCl₃) showed a doublet centered at 3.75δ(J=11.5c.ps.,6H) for ##EQU5## a triplet centered at 3.11δ (4H) for --CH₂ --CH₂--, a doublet centered at 3.14δ(J=23 cps, 2H) ##EQU6## and a multiplet6.7-7.4δ (3H) for thienyl ring protons

In the same manner dimethyl 2-oxo-4-(3-thienyl) butyl phosphonate may beprepared from methyl 3-(3-thienyl) propionate. This is also a suitablestarting material in the preparation of17-(3-thienyl)-ω-trisnorprostaglandins of the A, E and F series viaexamples 3-20. In the same manner starting materials suitable forconversion to 18, 19 or 20 α or β-thienyl substituted prostaglandins bythe procedure of Examples 1-20 can be synthesize from the appropriateesters.

EXAMPLE 362-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-5-(2-thienyl)-trans-1-penten-1-yl)-cyclopent-1α-yl]acetic acid, γ-lactone (3b)

Dimethyl 2-oxo-4-(2-thienyl)butylphosphate (2b) (2.81g, 7.5 mmole) in100 ml anhydrous ether was treated with 3.32 ml. (7.5 mmole) 2.26 Mn-butyllithium in n-hexane (Alfa Inorganics, Inc.) in a dry nitrogenatmosphere at room temperature. After 5 min. of stirring, an additional200 ml. of anhydrous ether was added followed by 2.0 g. (5.7 mmole)2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-formylcyclopentan-1α-yl]aceticacid, γ-lactone in one portion and 20 ml. anhydrous ether. After 35minutes the reaction mixture was quenched with 0.5 ml. glacial aceticacid and washed with 100 ml. saturated sodium bicarbonate solution (4x), 100 ml water (2 x), 100 ml. saturated brine (1 x), dried (MgSo₄) andevaporated to yield an oil which crystallized from CH₂ Cl₂ -hexane togive 2.4 g.2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-5-(2-thienyl)-trans-1-penten-1yl)cyclopent-1α-yl]acetic acid, γ-lactone (3b) m.p. 121°-123°.

The ir spectrum (KBr) of the product exhibited adsorbtion bands at 1776cm⁻ ¹ (strong), 1710 cm⁻ ¹ (strong), 1676 cm⁻ ¹ (medium and 1636 cm⁻ ¹.

The product of this example (3b) may be converted to 13,14dihydro-17-(2-thienyl)-ω-trisnorprostaglandins of the A, E or F seriesthrough the procedures of examples 10, 12-13 and 15-18. The product (3b)may also be converted to 15-loweralkyl-17-(2-thienyl)-ω-trisnorprostaglandins of the A, E or F series bythe procedures of examples 4-20.15-lower-alkyl-13,14dihydro-17-(2-thienyl)-ω-trisnorprostaglandins ofthe A, E or F series may be obtained from (3b) by the procedures ofexamples 10-13 and 14-18.

EXAMPLE 372-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (4b) and2[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone-(5b)

To a solution of 4.53 g (9.3 mmole)2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-5(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (3b) in 28 ml dry 1,2-dimethoxyethan in a dry nitrogenatmosphere at ambient temperature was added dropwise 9.3 ml of a 0.5 Mzinc borohydride solution. After stirring at room temperature for 45minutes, a saturated sodium bitartrate solution was added dropwise untilhydrogen evolution ceased. The reaction mixture was allowed to stir for5 minutes at which time 300 ml dry methylene chloride was added. Afterdrying (MgSO₄) and concentrating (water aspirator), the resultantsemisolid was purified by column chromatography on silica gel (Baker"Analyzed" Reagent 60-200 mesh) using ether as eluent. After elution ofless polar impurities, a fraction containing 1.44 g2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (4b), a 200 mg fraction of mixed (4b) and (5b) andfinally a fraction (1.72 g) of2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (55) was obtained.

The ir spectrum (CHCl₃) of 4b and 5b had strong carbonyl adsorbtions at1765 at 1709 cm.sup.⁻¹ and an adsorbtion at 970 cm.sup.⁻¹ for the transdouble bond.

EXAMPLE 382-[3α,5α-Dihydroxy-2β-(3α-hydroxy-5-(2-thienyl)-trans-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (6b)

A heterogeneous mixture of 1.44 g (2.95 mmole) of2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (4b), 16 ml. of absolute methanol and 75 mg of finelypowdered, anhydrous potassium carbonate was stirred at room temperatureovernight, then cooled to 0°. To the cooled solution was added 1.0 ml(1.0 mmole) of 1.0N aqueous hydrochloric acid. After stirring at 0° foran additional 10 minutes, 10 ml. of water was added with concomitantformation of methyl p-phenylbenzoate which was collected by filtration.The filtrate was saturated with sodid sodium chloride, extracted wihethyl acetate (4 × 20 ml.), the combined organic extracts were washedwith saturated sodium bicarbonate (10 ml.), dried (MgSO₄) andconcentrated to give 839 mg (92%) of crystalline,2-[3α,5α-dihydroxy-2β-(3α-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone(6b), m.p. 98°-100°.

The ir spectrum (CHCl₃) exhibited a strong adsorption at 1765 cm.sup.⁻¹for the lactone carbonyl and medium adsorption at 970 cm.sup.⁻¹ for thetrans-double bond.

EXAMPLE 392-[3α,5α-Dihydroxy-2β-(3β-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (6'b)

A heterogeneous mixture of 1.72 g. (3.52 m mole) of2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (4b), 20 ml. of absolute methanol and 90 mg. of finelypowdered, anhydrous potassium carbonate was stirred at room temperaturefor 18 hours, than cooled to 0°. To the cooled solution was added 1.0ml. (2.0° mmole) of 1.0N aqueous hydrochloric acid. After stirring at 0°for an additional 10 minutes, 15 ml. of water was added with concomitantformation of methyl p-phenylbenzoate which was collected by filtration.The filtrate was saturated with solid sodium chloride, extracted withethyl acetate (4 × 10 ml.), the combine organic extracts were washedwith saturated sodium bicarbonate (10 ml.) dried (MgSO₄) andconcentrated to give 967 mg. (90%) of viscous, oily2-[3α,5α-dihydroxy-2β-(3β-hydroxy-5-(2-thienyl)trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (6'b).

The ir spectrum (CHCl₃) exhibited a strong adsorption at 1768 cm.sup.⁻¹for the lactone carbonyl and medium adsoprtion at 968cm.sup.⁻¹ for thetrans-double bond.

EXAMPLE 402-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2-yloxy)-2β-(3.alpha.-{tetrahydropyran-2-yloxy}-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (7b):

To a solution of 839 mg (2.72 mmole)2-[3α,5α-dihydroxy-2β-(3α-hydroxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (6b) in 15 ml anhydrous methylenechloride and 0.75 of 2,3-dihydropyran at 0° in a dry nitrogen atmospherewas added 9 mg p-toluenesulfonic acid monohydrate. After stirring for 15minutes, the reaction mixture was combined with 200 ml ether, the ethersolution washed with saturated sodium bicarbonate (1 × 25 ml) and thensaturated brine (1 × 25 ml), dried (MgSO₄) and concentrated to yield1.28 (<100%) crude2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1.alpha.-yl]aceticacid, γ-lactone (7b).

The ir (CHCl₃) spectrum has a strong adsorbtion at 965 cm.sup.⁻¹ for thetrans-double bond.

The product of this example (7b) may be converted to13,14-dihydro-17-(2-thienyl)-ω-trisnorprostaglandins of the A, E or Fseries through the procedures of examples 10, 12, 14-18.

EXAMPLE 412-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3β-(tetrahydropyran-2-yloxy)-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (7'b)

To a solution of 967 mg. (3.14 m mole)2-[3α,5α-dihydroxy-2β-(3β-hydroxy-5-(2-thienyl-trans-1-penten-1-yl)cyclopent-1a-yl]aceticacid, γ-lactone (6'b) in 10 ml. anhydrous methylene chloride and 0.85ml. of 2,3-dihydropyran at 0° in a dry nitrogen atmosphere was added 10mg. p-toluenesulfonic acid monohydrate. After stirring for 15 minutes,the reaction mixture was combined with 100 ml. ether, the ether solutionwashed with saturated sodium bicarbonate (1 × 15 ml), then saturatedbrine (1 × 15 ml), then saturated brine (1 × 15 ml.), dried (MgSO₄) andconcentrated to yield 1.47 g. (>100%)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-β-(3β-(tetrahydropyran-2-yloxy)5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (7'b), which after crystallization from etherhexane hadmp. 80°-82°.

The ir (CHCl₃) spectrum has a strong adsorbtion at 960 cm.sup.⁻¹ for thetrans-double bond.

EXAMPLE 422-[5α-Hydroxy-3α-(tetrahydropyran2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-thienyl)-trans-1-penten-yl)cyclopent-1α-yl]acetaldehyde,γ-hemiacetal (8b)

A solution of 1.28 g (2.7 mmole) of2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1.alpha.-yl]aceticacid, γ-lactone (7b) in 13 ml dry toluene was cooled to -78° in a drynitrogen atmosphere. To this cooled solution was added 3.7 ml of 0.8 Mdiisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise atsuch a rate so that the internal temperature never rose above -65° (15minutes). After an additional 45 minutes of stirring at -78°, anhydrousmethanol was added until gas evolution ceased and the reaction mixturewas allowed to warm to room temperature. The reaction mixture wascombined with 150 ml ether, washed with 50% sodium potassium tartratesolution (4 × 20 ml), dried Na₂ SO₄) and concentrated to a quantitativeyield of oily 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1-yl]acetaldehyde,γ-hemiacetal (8b).

EXAMPLE 432-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3β-(tetrahydropyran-2-yloxy)-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetaldehyde,γ-hemiacetal (8'b)

A solution of 1.47 g (3.1 m mole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3β-(tetrahydropyran-2-yloxy)5-(2-thienyl)trans-1-penten-1-yl)cyclopent-1α-yl] acetic acid, γ-lactone (7'b) in 15ml. dry toluene was cooled to -78°, in a dry nitrogen atmosphere. Tothis cooled solution was added 4.25 ml. of 0.8M diisobutylaluminumhydride in n-hexane (Alfa Inorganics) dropwise at such a rate so thatthe internal temperature never rose above -65° (15 minutes). After anadditional 45 minutes of stirring at -78°, anhydrous methanol was addeduntil gas evolution ceased and the reaction mixture was allowed to warmto room temperature. The reaction mixture was combined with 100 ml.ether, washed with 50% sodium potassium tartrate solution (4 × 20 ml),dried (Na₂ SO₄) and concentrated to yield 1.38 g.2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3β-tetrahydropyran-2-yloxy-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetaldehyde,γ-hemiacetal (8'b).

EXAMPLE 449α-Hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl-cis-5-trans-13-ω-trisnorprostadienoic acid (9b)

To a solution of 1.8 g (4.04 mmole)(4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogenatmosphere in 8.0 ml dry dimethyl sulfoxide was added 3.5 ml (7.8 mmole)of a 2.2M solution of sodium methylsufinylmethide in dimethyl sulfoxide.To this red ylide solution was added dropwise a solution of 717 mg (1.5mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-thienyl)-trans-1-penten-1-yl]acetaldehyde,γ-hemiacetal (8b) in 5.0 ml dry dimethyl sulfoxide over a period of 20minutes. After an additional 2 hours stirring at room temperature, thereaction mixture was poured into ice water. The basic aqueous solutionwas washed twice with ethyl acetate (20 ml.) and acidified to pH 3 with10% aqueous hydrochloric acid. The acidic solution was extracted withethyl acetate (3 × 20 ml) and the combined organic extracts washed oncewith water (10 ml.), dried (MgSO₄ ) and evaporated to a solid residue.This solid residue was triturated with ethyl acetate and filtered. Thefiltrate was purified by column chromatography on silica gel (Baker"Analyzed" Reagent 60-200 mesh) using ethyl acetate as eluent. Afterremoval of high R_(f) impurities, 260 mg of 9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid (9b) was collected.

The product of this example (9b) can be converted to17-(2-thienyl)-ω-trisnorprostaglandins of the F series (F₂.sub.α,F₁.sub.α, F₀.sub.α) via the procedures of examples 10, 19 and 20.

EXAMPLE 45

9α-Hydroxy-11α,15β-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid (9'b)

To a solution of 1.8 g (4.05 mmole)(4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogenatmosphere in 5.0 ml dry dimethyl sulfoxide was added 3.2 ml (7.0 mmole)of a 2.2M solution of sodium methylsulfinylmethide in dimethylsulfoxide.To this red ylide solution was added dropwise a solution of 717 mg (1.34mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-thienyl)-trans-1-penten-1-yl)cylcopent-1.alpha.-yl]acetalehyde, γ-hemiacetal (8'b) in 5.0 ml dry dimethyl sulfoxideover a period of 20 minutes. After an additional 2 hours stirring atroom temperature, the reaction mixture was poured into ice water. Thebasic aqueous solution was washed twice with ethyl acetate (20 ml.) andacidified to pH ˜3 with 10% aqueous hydrochloric acid. The acidicsolution was extracted with ethyl acetate (3 × 20 ml) and the combinedorganic extracts washed once with water (10 ml.), dried (MgSO₄) andevaporated to a solid residue. This solid residue was triturated withethyl acetate and filtered. The filtrate was purified by columnchromatography on silica gel (Baker "Analyzed" Reagent 60-200 mesh)using ethyl acetate as eluent. After removal of high R_(f) impurities,740 mg of9α-hydroxy-11α,15β-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (9'b) was collected.

EXAMPLE 469-Oxo-11α-15α-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (10b)

To a solution cooled to -10° under nitrogen of 250 mg (.445 mmole)9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (9b) in 10 ml. reagent grade acetone was addeddropwise 0.18 ml. (.487 mmole) of Jones' reagent. After 20 minutes at-10°, 0.2 ml. 2-propanol was added and the reaction mixture was allowedto stir an additional 5 minutes at which time it was combined with 75ml. ethyl acetate, washed with (3 × 10 ml), dried (MgSO₄) andconcentrated to give 240 mg. of9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (10b).

EXAMPLE 479-Oxo-11α,15β-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (10'b)

To a solution cooled to -10° under nitrogen of 640 mg (1.14 mmole)9α-hydroxy-11α,15β-bis-(tetrahydropyran-2-yloxy)-17(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (9'b) in 9.2 ml. reagent grade acetone was addeddropwise to 0.502 ml. (1.25 mmole) of Jones' reagent. After 20 minutesat -10°, 0.5ml 2-propanol was added and the reaction mixture was allowedto stir an additional 5 minutes, at which time it was combined with 75ml. ethyl acetate, washed with water (3 × 10 ml.), dried (MgSO.sub. 4)and concentrated to give 500 mg. of9-oxo-11α,15β-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (10'b).

EXAMPLE 489-Oxo-11α,15α-dihydroxy-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (11b)

A solution of 240 mg. (0.334 mmole)9-oxo-11α,15α-bis-tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (10b) in 3.0 ml. of a 65:35 mixture of glacial aceticacid:water was stirred under nitrogen at 25° for 18 hours and then wasconcentrated by rotary evaporation. The resultant crude oil was purifiedby column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh)using ethyl acetate as eluent. After elution of less polar impurities,the oily 9-oxo-11α,15α-dihydroxy-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (11b) weighing 100 mg. was collected.

The product of this example (11b) can be converted to 17-(2-thienyl)-ω-trisnorprostaglandin E₁, E_(O), A₂, A₁ and A₀ via the procedures ofexamples 19, 20 and 12.

Biological activity: Guinea pig uterus 33; rat uterus 50; histamineaerosol test 0; dog blood pressure 10.

EXAMPLE 499-Oxo-11α,15β-dihydroxy-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoic acid (11'b)

A solution of 500 mg. (.893 mmole)9-oxo-11α,15β-bis-tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-ω-tetranorprostadienoicacid (10'b) in 7.0 ml. of a 65:35 mixture of glacial acetic acid:waterwas stirred under nitrogen at 25° for 18 hours and then was concentratedby rotary evaporation. The resultant crude oil was purified by columnchromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) usingethyl acetate as eluent. After elution of less polar impurities, thesemisolid9-oxo-11α,15β-dihydroxy-17-(2-thienyl)-cis-5-trans-13-ω-trisnorprostadienoicacid (11'b) weighing 215 mg was collected.

EXAMPLE 50 Dimethyl 2-oxo-4-(2furyl)butylphosphonate (2C)

A solution of 25 g (0.21 mole) dimethyl methylphosphonate (Aldrich) in300 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogenatmosphere. To the stirred phosphonate solution was added 80 ml of 2.67M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwiseover a period of 18 minutes at such a rate that the reaction temperaturenever rose above -65°. After an additional 5 minutes stirring at -78°,16.0 g (.104 mole) methyl 3-(2-furyl)propionate was added dropwise at arate that kept the reaction temperature less than -70° (20 minutes).After 3.5 hours at -78° the reaction mixture was allowed to warm toambient temperature, neutralized with 6 ml acetic acid and rotaryevaporated to a white gel. The gelatinous material was taken up in 75 mlwater, the aqueous phase extracted with 100 ml portions of chloroform(3x), the combined organic extracts were backwashed (50 cc H₂ O), dried(MgSO₄), and concentratead (water aspirator) to a crude residue anddistilled, b.p. 148-50° (0.5 mm) to give 8.4 g dimethyl2-oxo-4-(2-furyl)butylphosphonate (2C).

The nmr spectrum (CDCl₃) showed a doublet centered at 3.73δ (J = 11.5cps, 6H) for ##EQU7## a singlet centered at 2.95δ(2H) for CH₂ --CH₂ --,a doublet centered at 3.12 δ (J = 23 cps, 2H) ##EQU8## and multiplets at5.96, 6.23 and 7.23 δ (1H each) for furan ring protons.

In a manner similar to the above, dimethyl2-oxo-4-(3-furyl)butylphosphonate may be obtained by substituting methyl3-(3-furyl) propionate for methyl 3-(2-furyl) propionate in the aboveexample. This compound is a suitable starting material for the synthesisof 17-(3-furyl)-ω-trisnorprostaglandins of the A, E or F series by theprocedures of example 2-20. In the same manner the dimethyl2-oxo-2-(3-furyl)ethyl phosphonate was prepared BP 140°C. (0.2 mm). Thisis a suitable starting material for the preparation of 13-14dihydro-15-(3-furyl)-ω-pentanorprostaglandins of the A, E or F series bythe procedure of examples 2 and 10-20.

In the same manner the dimethyl-2-oxo-2-(2-thienyl)ethyl phosphonate canbe prepared. This is a suitable starting material for the synthesis of13,14-dihydro 15α-thienyl-ω-pentanorprostaglandins of the A, E or Fseries by the procedure of examples 2 and 10-20.

In a similar manner dimethyl 2-oxo-3(2-furyl)propyl phosphonate,dimethyl-2-oxo-5-(2-furyl)pentylphosphonate,dimethyl-2-oxo-6(2-furyl)-hexylphosphonate anddimethyl-2-oxo-7-(2-furyl)-heptylphosphonate may be prepared from theappropriate starting materials. These are suitable starting materialsfor the preparation of the 16, 18, 19 and 20 α-furyl substitutedprostaglandin of this invention by the procedure of examples 2-20. The3-furyl derivatives are prepared in the same manner as the 2-furylderivatives from the appropriate starting materials.

EXAMPLE 512-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-5-(2-furyl)-trans-1-penten-1-yl)-cyclopent-1α-yl]AceticAcid, γ-lactone (3C)

Dimethyl 2-oxo-4-(2-furyl) butylphosphonate (2C) (5.2 g. 21.1 mmole) wasadded to a mixture of 230 ml anhydrous DME and 57% NaH (860 mg, 20mmole), and heated to reflux until no hydrogen was given off (1 hour).After cooling, 5.2 g (21 mmole)2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-formylcyclopent -1α-yl]aceticacid, γ-lactone was added in one portion, followed by 100 ml DME. After1 hour the reaction mixture was quenched with 2 ml glacial acetic acid,filtered and concentrated to dryness. The residue dissolved in ethylacetate and was washed with 100 ml saturated sodium bicarbonate solution(4 x), 100 ml water (2x), 100 ml saturated brine (1 x), dried (MgSO₄)and evaporated to yield 6.02 g2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (3C) as an oil after columnchromatography (Silica gel, Baker, 60-200 mesh).

The ir spectrum (CHCl₃) of the product exhibited absorbtion bands at1774 cm⁻ ¹ (strong), 1710 cm⁻ ¹ (strong), 1670 cm⁻ ¹ (medium) and 1625cm⁻ ¹ (medium) attributable to the carbonyl groups and at 973 cm⁻ ¹ forthe trans double bond.

The product of this example (3C) may be converted to13,14-dihydro-17-(2-furyl)-ω-trisnorprostaglandins of the A, E or Fseries through the procedures of examples 10 12-13, and 15-18.

The product (3C) may also be converted to 15-loweralkyl-17-(2-furyl)-ω-trisnorprostaglandins of the A, E or F series bythe procedures of examples 4-20.

15-lower alkyl-17-(2-furyl)-ω-tetranorprostaglandins of the A, E or Fseries may be obtained from (3C) via the procedures of examples 10-13and 15-18. In a similar manner the2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-3-(3-furyl-trans-1-propen-1-yl)-cyclopent-1α-yl]aceticacid, γ-lactone was prepared m.p. 140°-141°C. IR 1715, 1775, 1625, 1675,975 cm⁻ ¹.

EXAMPLE 522-[3α-p-Phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (4C) and2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (5C)

To a solution of 5.97 g (12.7 mmole)2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3-oxo-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γlactone (3C) in 3 ml dry1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperaturewas added dropwise 12.7 ml of a 0.5 M zinc borohydride solution. Afterstirring at room temperature for 45 minutes, a saturated sodiumbitartrate solution was added dropwise until hydrogen evolution ceased.The reaction mixture was allowed to stir for 5 minutes, at which time300 ml dry methylene chloride was added. After drying (MgSO₄) andconcentrating (water aspirator), the resultant semisolid was purified bycolumn chromatography on silica gel (Baker "Analyzed" Reagent 60-200mesh) using ether as eluent. After elution of less polar impurities, afraction containing 2.26 g2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (4C), a 270 mg fraction of mixed 4C and 5C andfinally a fraction (2.2 g) of2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3β-hydroxy-5-(2-furyl)-trans-1-penten-yl)cyclopent-1α-yl]aceticacid, γ-lactone (5C).

The ir spectrum (CHCl₃) of 4C and 5C had strong carbonyl absorbtions at1770 and 1710 cm⁻ ¹ and an absorbtion at 970 cm⁻ ¹ for the trans doublebond.

EXAMPLE 532-[3α,5α-Dihydroxy-2β-(3α-hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]aceticacid, γ-lactone (6C)

A heterogeneous mixture of 2.26 g (4.8 mmole) of2-[3α-p-phenylbenzoyloxy-5α-hydroxy-2β-(3α-hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (4C), 26 ml. of absolutemethanol and 660 mg of finely powdered, anhydrous potassium carbonatewas stirred at room temperature for 1 hour, then cooled to 0°. To thecooled solution was added 9.6 ml of 1.0N aqueous hydrochloric acid.After stirring at 0° for an additional 10 minutes, 20 ml. of water wasadded with concomitant formation of methyl p-phenylbenzoate which wascollected by filtration. The filtrate was saturated with solid sodiumchloride, extracted with ethyl acetate (4 × 20 ml.), the combinedorganic extracts were washed with saturated sodium bicarbonate (10 ml.),dried (MgSO₄) and concentrated to give 1.02 g of viscous, oily2-[3α,5α-dihydroxy-2β-(3α-hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (6C).

The ir spectrum (CHCl₃) exhibited a strong absorption at 1765 cm⁻ ¹ forthe lactone carbonyl and medium absorption at 960 cm⁻ ¹ for thetrans-double bond.

EXAMPLE 542-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (7C)

To a solution of 1 gm (3.42 mmole) 2-[3 α,5α-dihydroxy-2β-(3α-hydroxy-5-(2-furyl)-trans-1-penten-yl)cyclopent-1α-yl]acetic acid, γ-lactone (6 C) in 5 mlanhydrous methylene chloride and Q93 ml of 2,3-dihydropyran at 0° in adry nitrogen atmosphere was added 10 mg p-toluenesulfonic acid,monohydrate. After stirring for 15 minutes, the reaction mixture wascombind with 100 ml ether, the ether solution washed with saturatedsodium bicarbonate (1 × 15 ml) then saturated brine (1 × 20 ml), dried(MgSO₄) and concentrated to yield 1.63 g (>100%) crude2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (7 C).

The ir (CHCl₃) spectrum has a strong absorption at 960 cm.sup.⁻¹. fortrans double bond.

The product of this example (7 C) may be converted to13,14-dihydro-17-(2-furyl)-ω-trishorprostaglandins of the A, E or Fseries through the procedures of examples 10, 12, 14-18.

EXAMPLE 552-[5α-Hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-furyl)-trans- 1-penten-1-yl)cyclopent-1α-yl]acetaldehyde,γ-hemiacetal (8C)

A solution of 1.6 g (3.4 mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-tetrahydropyran-2-yloxy- 5-(2-furyl)-trans-1-pentene-1-yl)cyclopent-1α-yl]acetic acid, γ-lactone (7C) in 16 ml drytoluene was cooled to -78° in a dry nitrogen atmosphere. To this cooledsolution was added 4.68 ml of 0.8M diisobutylaluminum hydride inn-hexane (Alfa Inorganics) dropwise at such a rate so that the internaltemperature never rose above -65° (15 minutes). After an additional 45minutes of stirring at -78°, anhydrous methanol was added until gasevolution ceased and the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was combined with 150 ml ether, washedwith 50% sodium potassium tartrate solution (4 × 20 ml), dried (Na₂ SO₄)and concentrated to a quantitative yield of oily2-[5α-hydroxy-3α-(tetrahydropyran -2-yloxy)-2β-{tetrahydropyran-2-yloxy}-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1-yl]acetaldehyde, γ-hemiacetal (8C).

EXAMPLE 56 9α-Hydroxy-11 α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-ω-trisnor-prostadienoic acid (9C)

To a solution of 3.36 g (7.6 mmole) (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 15.0 ml drydimethyl sulfoxide was added 7.0 ml (14.0 mmole) of a 2.0M solution ofsodium methylsufinylmethide in dimethyl sulfoxide. To this red ylidesolution was added dropwise a solution of 1.3 g (2.81 mmole)2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2β-(3α-{tetrahydropyran-2-yloxy}-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1α-yl]acetaldehyde, γ-hemiacetal (8 C) in 5.0 mldry dimethyl sulfoxide over a period of 20 minutes. After an additional2 hours stirring at room temperature, the reaction mixture was pouredonto ice water. The basic aqueous solution was washed twice with ethylacetate (20 ml.) and acidified to pH ˜3 with 10% aqueous hydrochloricacid. The acidic solution was extracted with ethyl acetate (3 × 20 ml)and the combined organic extracts washed once with water (10 ml.) dried(MgSO₄) and evaporated to a solid residue. This solid residue wastriturated with ethyl acetate and filtered. The filtrate was purified bycolumn chromatography on silica gel (Baker "Analyzed" Reagent 60-200mesh) using ethyl acetate as eluent. After removal of high R_(f)impurities, 1.53 g of 9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13ω-trisnor-prostadienoic acid (9C) was collected.

EXAMPLE 57 9-Oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-ω-trisnor-prostadienoic acid (10 C)

To a solution cooled to -10° under nitrogen of 1.1g (2.01mmole)9α-hydroxy-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-ω-trisnor-prostadienoic acid (9C) in 20 ml. reagent gradeacetone was added dropwise to 0.88 ml (2.2 mmole) of Jones' reagent.After 20 minutes at -10°, 0.260 ml. 2-propanol was added and thereaction mixture was allowed to stir an additional 5 minutes at whichtime it was combind with 75 ml. ethyl acetate, washed with water (3 × 10ml.), dried (MgSO₄) and concentrted to give 425 mg of9-oxo-11α,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-ω-trisnor-prostadienoic acid (10C).

EXAMPLE 58 9-Oxo-11α,15α-dihydroxy-17-(2-furyl)-cis-5-trans-13-ω-trisnor-prostadienoic acid (11C)

A solution of 425 mg (0.782 mmole)9-oxo-11α,15α-bis-tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-)-cis-5-trans-13-ω-trisnor-prostadienoicacid (10C) in 300 ml. of a 65:35 mixture of glacial acetic acid:waterwas stirred under nitrogen at 25° for 18 hours, then was concentrated byrotary evaporation. The resultant crude oil was purified by columnchromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) usingethyl acetate as eluent. After elution of less polar impurities, thecrystalline 9-oxo-11α,15α-dihydroxy-17-(2-furyl)-cis-5-trans-13-ω-trisnor-prostadienoic acid (11C) mp 98°-99° weighing 204 mgwas collected.

The product of this example (11C) can be converted to 17-(2-furyl)-ω-trisnorprostaglandins-E₁, E_(O), A₂, A₁ and A_(O) via the procedures ofexamples 19; 20, and 12.

EXAMPLE 59 9α,11α,15α-Trihydroxy-17-(2-furyl)-cis-5-trans-13-ω-trisnorprostadienoic acid(12C)

A solution of 700 mg. (0.334 mmole)9α-hydroxy-11α,15α-bis-tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-ω-trisnorprostadienoicacid (9 C) in 5 ml. of a 65:35 mixture of glacial acetic acid:water wasstirred under nitrogen at 25° for 20 hours, then was concentrated byrotary evaporation. The resultant crude oil was purified by columnchromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) usingethyl acetate as eluent. After elution of less polar impurities, theoily9α,11α,15α-trihydroxy-17-(2-furyl)-cis-5-trans-13ω-trisnorprostadienoicacid (12C) weighing 108 mg. was collected.

The ir (CHCl₃) had a carbonyl absorbtion at 1710 cm.sup.⁻¹ and a transdouble bond absorption at 965 cm.sup.⁻¹.

The product of this example (12C) can be converted to17-(2-furyl)-107-trisnorprostaglandins F₁.sub.α and F_(O).sub.α via theprocedures of examples 19 and 20.

What is claimed is:
 1. A compound of the structure: ##SPC12##wherein Aris α- or β-furyl or α- or β-thienyl; R is hydrogen or lower alkyl; n isan integer from 1 to 5; W and L are each a single bond or cis doublebond; Z is a trans double bond; M is keto, ##EQU9## N is hydrogen orα-hydroxyl; and wherein L, M and N are so selected as to complete thestructure of a prostaglandin of the A, E or F series.
 2. The compound ofclaim 1 wherein W is a cis double bond and Z is a trans double bond. 3.The compound of claim 1 wherein W is a single bond and Z is a transdouble bond.
 4. The compound of claim 1 wherein Ar is α-thienyl, n is 1and said prostaglandin is PGE1.
 5. The compound of claim 1 wherein Ar isa α-thienyl, n is 1, and said prostaglandin is PGE₂.
 6. The compound ofclaim 2 wherein Ar is β-thienyl, n is 1, and said prostaglandin is PGE₂.7. The compound of claim 2 wherein Ar is α-thienyl, n is 2, and saidprostaglandin is PGE₂.
 8. The compound of claim 2 wherein Ar is α-furyl,n is 2, and said prostaglandin is PGE₂.
 9. The compound of claim 2wherein Ar is α-furyl, n is 2, and said prostaglandin is PGF₂.sub.α. 10.The compound of claim 2 wherein Ar is α-thienyl, n is 2, and saidprostaglandin is PGF₂.sub.α.
 11. The compound of claim 2 wherein Ar isα-furyl, n is 2, and said prostaglandin is PGF₂.sub.β.
 12. A compound ofthe structure: ##SPC13##wherein Ar is α- or β-furyl; α- or 8-thienyl; Ris hydrogen or lower alkyl; n is an integer from 1 to 5; W is a singlebond or cis double bond; and Z is a trans double bond.
 13. A compound ofthe structure: ##SPC14##wherein Ar is α- or β-furyl; α- or β-thienyl; Ris hydrogen or lower alkyl; n is an integer from 1 to 5; W is a singlebond or cis double bond; and Z is a trans double bond.
 14. A compound ofthe structure: ##SPC15##wherein Ar is α- or β-furyl; α- or β-thienyl; Ris hydrogen or lower alkyl; n is an integer from 1 to 5; W is a singlebond or cis double bond; and Z is a trans double bond.